VITEK 2 AST-Streptococcus Meropenem (=0.06 - =4 µg/mL)

{0} [LOGO] FDA U.S. FOOD & DRUG ADMINISTRATION ### 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY ASSAY ONLY ### I Background Information: A 510(k) Number K260283 B Applicant bioMérieux, Inc C Proprietary and Established Names VITEK 2 AST-Streptococcus Meropenem (≤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 Meropenem (≤0.06 - ≥4 μg/mL) for susceptibility testing of Streptococcus pneumoniae, 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 {1} # **B Measurand:** Meropenem ≤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* Meropenem (≤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* Meropenem (≤0.06 - ≥4 μg/mL) is a quantitative test. Testing is indicated for *Streptococcus pneumoniae*, *Streptococcus* spp. β-Hemolytic Group and *Streptococcus* spp. Viridans Group, as recognized by the FDA Susceptibility Test Interpretive Criteria (STIC). VITEK 2 AST-*Streptococcus* Meropenem (≤0.06 - ≥4 μg/mL) has demonstrated acceptable performance with the following organisms: *Streptococcus pneumoniae* *Streptococcus* spp. β-Hemolytic Group (*Streptococcus agalactiae*, *Streptococcus canis*, *Streptococcus dysgalactiae* ssp. *equisimilis*, *Streptococcus equisimilis* ssp. *zooepidemicus*, *Streptococcus pyogenes*) *Streptococcus* spp. Viridans Group (*Streptococcus anginosus*, *Streptococcus constellatus*, *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 K260283 - Page 2 of 17 {2} If Streptococcus anginosus does not provide a result for the VITEK2 AST-ST test cards but growth is observed on the purity plate, do not retest the isolate on the VITEK2 Systems and perform an alternative method of testing prior to report of results. 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: Meropenem (mem02n): Streptococcus spp. β-Hemolytic Group, Streptococcus spp. Viridans Group (except Streptococcus mitis, Streptococcus oralis, Streptococcus parasanguinis) Due to the occurrence of minor errors (resulting in a category agreement below 90% for the manual dilution options), perform an alternative method of testing prior to reporting of results generated with the manual dilution options for the following antibiotic/organism combination: Meropenem (mem02n): Streptococcus pneumoniae (if critical to patient care). # 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 minimum inhibitory concentration or “MIC” values for the antimicrobial agent. At the completion of the incubation cycle, a report is generated that contains K260283 - Page 3 of 17 {3} the MIC value along with the interpretive category result for each antimicrobial contained on the card. VITEK 2 AST-ST Meropenem has the following concentrations in the card: 0.12, 0.25, 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 Meropenem 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 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 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: K260283 | Predicate: K232201 | | --- | --- | --- | | Device Trade Name | VITEK 2 AST-Streptococcus Meropenem (≤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 Meropenem (≤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 | 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 | K260283 - Page 4 of 17 {4} | | a laboratory aid in the determination of *in vitro* susceptibility to antimicrobial agents. VITEK 2 AST-*Streptococcus* Meropenem (≤0.06 - ≥4 μg/mL) is a quantitative test. Testing is indicated for *Streptococcus pneumoniae*, *Streptococcus* spp. β-Hemolytic Group and *Streptococcus* spp. Viridans Group, as recognized by the FDA Susceptibility Test Interpretive Criteria (STIC). VITEK 2 AST-*Streptococcus* Meropenem (≤0.06 - ≥4 μg/mL) has demonstrated acceptable performance with the following organisms: *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 anginosus*, *Streptococcus constellatus*, *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 | 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* *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. | | --- | --- | --- | K260283 - Page 5 of 17 {5} | | 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 | | Test Card | VITEK 2 *Streptococcus* Susceptibility Test Card | Same | | **General Device Characteristic Differences** | | | | Antimicrobial Agent | Meropenem | Penicillin | | Antimicrobial Concentrations | 0.12, 0.25, 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 equisimilis* ssp. *zooepidemicus*, *Streptococcus pyogenes*) *Streptococcus* spp. Viridans Group (*Streptococcus anginosus*, *Streptococcus constellatus*, *Streptococcus cristatus*, *Streptococcus gallolyticus* ssp. *gallolyticus*, *Streptococcus gordonii*, *Streptococcus infantarius* ssp. *infantarius*, *Streptococcus mitis*, *Streptococcus oralis*, *Streptococcus parasanguinis*, *Streptococcus salivarius* ssp. | Beta hemolytic *Streptococci* groups C and G *Streptococcus pyogenes* *Streptococcus agalactiae* *Streptococcus viridans* group *Streptococcus pneumoniae* | K260283 - Page 6 of 17 {6} | | salivarius, Streptococcus sanguinis, Streptococcus uberis, Streptococcus vestibularis) | | | --- | --- | --- | ### 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 Meropenem when revised breakpoints for meropenem are published on the FDA STIC webpage. The breakpoint change protocol included with the submission indicated that if specific criteria are met, bioMérieux, Inc. will update the VITEK 2 AST-Streptococcus Meropenem 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 Meropenem was conducted at three external sites using a panel of sixteen isolates (7 S. pneumoniae, 3 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 K260283 - Page 7 of 17 {7} 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. All 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 is shown in Table 1. Table 1. Reproducibility Performance of VITEK 2 AST-Streptococcus Meropenem* | | VITEK 2 | | VITEK 2 Compact | VITEK COMPACT PRO | | --- | --- | --- | --- | --- | | | Auto-Dilution | Manual Dilution | Manual Dilution | Manual Dilution | | Best-Case | 100% | 100% | 100% | 99.6% | | Worst-Case | 100% | 100% | 100% | 99.6% | *Streptococcus pneumoniae and Streptococcus spp. Viridans Group The MIC results for Streptococcus spp. \( \beta \) -Hemolytic Group (6 isolates) were off-scale, which is consistent with current epidemiology. The VITEK 2 AST-Streptococcus Meropenem reporting range includes sufficient serial two-fold dilutions below the “susceptible-only” breakpoint (meropenem has only a “susceptible” category for Streptococcus spp. \( \beta \) -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): K260283 - Page 8 of 17 {8} ## 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 Meropenem 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 Meropenem 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 Table 2. Quality Control Results for VITEK 2 AST-Streptococcus Meropenem | 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* | | ≤0.0078125 | | 1 | | | | | | | | | | 0.015625 | | | | | | | | | | | | 0.03125 | | 15 | | 5 | | 5 | | | | | ≤0.0625 | 0.0625 | 163 | 175 | 76 | 85 | 73 | 85 | 1 | 23 | | | 0.125 | 0.125 | 28 | 3 | 16 | 2 | 19 | 2 | 22 | | | | 0.25 | 0.25 | | | | | | | | | | Expected Results: 0.03-0.25 μg/mL | 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 Meropenem 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 Meropenem 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 0.25-1 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 0.25-1 μg/mL with VITEK 2/auto- K260283 - Page 9 of 17 {9} 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 meropenem 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. ### Growth Failure Rate: A total of 795 clinical and challenge isolates were tested by VITEK 2 AST-ST Meropenem. There were 13 growth failures recorded, and 782 isolates have VITEK 2 AST results available. Eleven (11) Streptococcus anginosus isolates failed to grow. To address the growth failure rate of S. anginosus, the following limitation is included in the device labeling: If Streptococcus anginosus does not provide a result for the VITEK2 AST-ST test cards but growth is observed on the purity plate, do not retest the isolate on the VITEK2 Systems and perform an alternative method of testing prior to report of results. ### 6. Assay Cut-Off: Not applicable. ### B Comparison Studies: ### 1. Method Comparison with Predicate Device: Testing of meropenem was performed at four external sites and one internal site. Results obtained with VITEK 2 AST-Streptococcus Meropenem were compared to results obtained with the CLSI broth microdilution reference panel. The MIC result range for the VITEK 2 AST-Streptococcus Meropenem is ≤0.06 - ≥4 μg/mL for S. pneumoniae, 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 K260283 - Page 10 of 17 {10} The VITEK 2 cards were inoculated with test organisms using the auto-dilution method (VITEK 2) and using 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 782 isolates (682 clinical isolates and 100 challenge isolates) were evaluated using auto-dilution and VITEK 2. Of these isolates, 49% were contemporary isolates (tested within six months of isolation) and 51 % were stock isolates (no specific time from isolation). The clinical isolates included: 303 S. pneumoniae isolates, 241 Streptococcus spp. β-Hemolytic Group isolates (98 Streptococcus agalactiae, 27 Streptococcus canis, 45 Streptococcus dysgalactiae ssp. equisimilis, 3 Streptococcus equi ssp. zooepidemicus, 68 Streptococcus pyogenes), and 138 Streptococcus spp. Viridans Group isolates (13 Streptococcus anginosus, 11 Streptococcus constellatus, 1 Streptococcus cristatus, 2 Streptococcus gallolyticus ssp. gallolyticus, 9 Streptococcus gordonii, 14 Streptococcus mitis, 3 Streptococcus oralis, 33 Streptococcus mitis/oralis, 30 Streptococcus parasanguinis, 10 Streptococcus salivarius ssp. salivarius, 5 Streptococcus sanguinis, 3 Streptococcus uberis, 2 Streptococcus vestibularis, 2 Streptococcus spp. Viridans Group, not differentiated) A total of 100 challenge isolates were evaluated at two external sites (VITEK 2 and VITEK 2 Compact) or one internal site (VITEK COMPACT PRO). The challenge isolates included: 38 S. pneumoniae, 45 β-Hemolytic Group Streptococcus spp. (26 Streptococcus agalactiae, 19 Streptococcus pyogenes), and 17 Streptococcus spp. Viridans Group isolates (1 Streptococcus gallolyticus ssp. gallolyticus, 1 Streptococcus gordonii, 1 Streptococcus infantarius ssp. infantarius, 9 Streptococcus mitis, 2 Streptococcus mitis/oralis, 2 Streptococcus oralis, 1 Streptococcus sanguinis). ### Clinical and Challenge Data – VITEK 2 Auto-Dilution The results obtained using the auto-dilution method of the VITEK 2 from the 782 total isolates (682 clinical isolates and 100 challenge isolates) are summarized in Table 3. Table 3. Performance of All Clinical and Challenge Isolates for Meropenem: VITEK 2 Auto-Dilution | | Total | #EA | %EA | Eval EA Total | Eval EA # | Eval EA% | #CA | %CA | #R/NS | #S | min | maj | vmj | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Streptococcus pneumoniae ≤0.25 (S), 0.5 (I), ≥1 (R) | | | | | | | | | | | | | | | Clinical | 303 | 297 | 98.0 | 66 | 60 | 90.9 | 285 | 94.1 | 35 | 247 | 17 | 0 | 1 | | Challenge | 38 | 38 | 100 | 38 | 38 | 100 | 23 | 60.5 | 20 | 3 | 15 | 0 | 0 | | Combined | 341 | 335 | 98.2 | 104 | 98 | 94.2 | 308 | 90.3 | 55 | 250 | 32 | 0 | 1 | | Streptococcus spp. β-Hemolytic Group ≤0.5 (S) | | | | | | | | | | | | | | | Clinical | 241 | 241 | 100 | 0 | 0 | NA | 241 | 100 | 0 | 241 | NA | 0 | 0 | | Challenge | 45 | 45 | 100 | 0 | 0 | NA | 45 | 100 | 0 | 45 | NA | 0 | 0 | | Combined | 286 | 286 | 100 | 0 | 0 | NA | 286 | 100 | 0 | 286 | NA | 0 | 0 | | Streptococcus spp. Viridans Group ≤0.5 (S) | | | | | | | | | | | | | | | Clinical | 138 | 133 | 96.4 | 39 | 34 | 87.2 | 135 | 97.8 | 7 | 131 | NA | 0 | 3 | | Challenge | 17 | 16 | 94.1 | 14 | 13 | 92.7 | 17 | 100 | 5 | 12 | NA | 0 | 0 | | Combined | 155 | 149 | 96.1 | 53 | 47 | 88.7 | 152 | 98.1 | 12 | 143 | NA | 0 | 3 | K260283 - Page 11 of 17 {11} 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 98.2% (Table 3). The CA was acceptable at 90.3% and there were thirty-two minor errors, zero major errors and one very major error (1.8%). For Streptococcus spp. β-Hemolytic Group evaluated with the auto-dilution method of the VITEK 2, the overall EA was acceptable at 100% (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. β-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: - Meropenem (mem02n): 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 96.1% (Table 3). The overall CA was acceptable at 98.1% and there were no potential major errors and three potential very major errors. Errors are considered potential errors since no other category is defined other than “susceptible”. When errors cannot be categorized as minor, adjustments are made to categorical errors by considering if the MIC values where the errors occur were in essential agreement with the reference method. All three potential very major errors have an MIC value that were in essential agreement with the reference method MIC value; therefore, the adjusted potential very major error rate is 0%, which is acceptable. When evaluating by individual species, S. parasanguinis had an EA of 87.5% (21/24) and CA of 91.7% (22/24) and no potential major errors and 2 potential very major errors. The two potential very major errors have an MIC value that were in essential agreement with the reference method MIC value; therefore, the adjusted potential very major error rate is 0%, which is acceptable. However, the EA performance was not acceptable. S. constellatus had an EA of 66.7% (2/3) and CA of 100% (3/3) with no potential errors, which was not acceptable. S. gordonii had an EA of 66.7% (2/3) and CA of 100% (3/3) with no potential errors, which is not acceptable. A supplemental study was performed to address the unacceptable EA performance of S. parasanguinis, S. constellatus, and S. gordonii with the auto-dilution method of the VITEK 2. K260283 - Page 12 of 17 {12} 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 of 100% (6/6) and CA of 100% (6/6) with no potential errors, which was acceptable. When the original and supplemental data were combined, S. parasanguinis had an EA of 90% (27/30) and CA of 93.3% (28/30) with no potential major errors and no adjusted potential very major errors when evaluated with the auto-dilution method of the VITEK 2, which was acceptable. Eight additional S. constellatus clinical isolates were tested in a supplemental study performed at one internal site. The supplemental S. constellatus testing had an EA and CA of 100% (8/8) with no potential errors, which was acceptable. When the original and supplemental data were combined, S. constellatus had an EA of 90.9% (10/11) and CA of 100% (11/11) with no potential errors when evaluated with the auto-dilution method of the VITEK 2, which was acceptable. Seven additional S. gordonii clinical isolates were tested in a supplemental study performed at one internal site. The supplemental S. gordonii testing had an EA of 100% (7/7) and CA of 100% (7/7) with no potential errors, which was acceptable. When the original and supplemental data were combined, S. gordonii had an EA of 90% (9/10) and CA of 100% (10/10) with no potential 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 96.1% (149/155) and CA of 98.1% (152/155) with no potential major errors and no potential adjusted very major errors, which was acceptable. Since only susceptible Streptococcus spp. Viridans 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: - Meropenem (mem02n): Streptococcus spp. Viridans Group (except Streptococcus mitis, Streptococcus oralis, Streptococcus parasanguinis) ### Challenge Data –VITEK 2, VITEK 2 Compact, and VITEK COMPACT PRO Manual Dilution The 100 challenge isolates were also evaluated at two external sites 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). Table 4. Performance of Challenge Isolates for Meropenem: VITEK 2, VITEK 2 Compact and VITEK COMPACT PRO Manual Dilution | VITEK 2 Systems | Total | #EA | %EA | Eval EA Total | Eval EA # | Eval EA% | #CA | %CA | #R/NS | #S | min | maj | vmj | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Streptococcus pneumoniae ≤0.25 (S), 0.5 (I), ≥1 (R) | | | | | | | | | | | | | | | VITEK 2 | 38 | 38 | 100 | 38 | 38 | 100 | 22 | 57.9 | 20 | 3 | 16 | 0 | 0 | K260283 - Page 13 of 17 {13} | VITEK 2 Compact | 38 | 38 | 100 | 38 | 38 | 100 | 23 | 60.5 | 20 | 3 | 15 | 0 | 0 | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | VITEK 2 COMPACT PRO | 38 | 38 | 100 | 37 | 37 | 100 | 22 | 57.9 | 20 | 3 | 16 | 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 2 COMPACT PRO | 45 | 45 | 100 | 0 | 0 | NA | 45 | 100 | 0 | 45 | NA | 0 | 0 | | Streptococcus spp. Viridans Group ≤0.5 (S) | | | | | | | | | | | | | | | VITEK 2 | 17 | 16 | 94.1 | 14 | 13 | 92.9 | 17 | 100 | 5 | 12 | NA | 0 | 0 | | VITEK 2 Compact | 17 | 16 | 94.1 | 14 | 13 | 92.9 | 17 | 100 | 5 | 12 | NA | 0 | 0 | | VITEK 2 COMPACT PRO | 17 | 16 | 94.1 | 15 | 14 | 93.3 | 16 | 94.1 | 5 | 12 | NA | 1 | 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. The overall performance of the VITEK 2 AST-Streptococcus Meropenem when testing S. pneumoniae with the manual dilution method was not acceptable with an EA of 100%, CA of 57.9% and sixteen (16) minor errors, and no major or very major errors. The overall performance of the VITEK 2 AST-Streptococcus Meropenem when testing S. pneumoniae with the VITEK 2 Compact was not acceptable with an EA of 100%, CA of 60.5% and fifteen (15) minor errors, and no major or very major errors. The overall performance of the VITEK 2 AST-Streptococcus Meropenem when testing S. pneumoniae with the COMPACT PRO was not acceptable with an EA of 100%, CA of 57.9% and sixteen (16) minor errors, and no major or very major errors (Table 4). To address the observed low CA performance with the manual dilution option of the VITEK 2 instruments, the following limitation was included in the device labeling. Due to the occurrence of minor errors (resulting in a category agreement below 90% for the manual dilution options), perform an alternative method of testing prior to reporting of results generated with the manual dilution options for the following antibiotic/organism combination: Meropenem (mem02n): Streptococcus pneumoniae (if critical to patient care). The overall performance of the VITEK 2 AST-Streptococcus Meropenem when testing Streptococcus spp. β-Hemolytic Group with the manual dilution method, VITEK 2 Compact K260283 - Page 14 of 17 {14} System, and the VITEK COMPACT PRO was acceptable with an EA and CA of 100%, and no potential major or very major errors (Table 4). Errors are considered potential errors since no other category is defined other than “susceptible”. The overall performance of the VITEK 2 AST-Streptococcus Meropenem when testing Streptococcus spp. Viridans Group with the manual dilution method and the VITEK 2 Compact System, the performance was acceptable with an EA of 94.1% and CA of 100%, with no potential major or very major errors. The overall performance of the VITEK 2 AST-Streptococcus Meropenem when testing Streptococcus spp. Viridans Group with manual dilution method and the VITEK COMPACT PRO was acceptable with an EA and CA of 94.1% with one (1) potential major error (8.3%) and no potential very major error (Table 4). When errors cannot be categorized as minor, adjustments are made to categorical errors by considering if the MIC values where the errors occur were in essential agreement with the reference method. The one potential major error had an MIC value that was not in essential agreement with the reference method MIC value; therefore, the adjusted potential major error rate is 8.3%. The one adjusted potential major error was due to a single S. gallolyticus ssp. gallolyticus isolate. Due to the limited. S. gallolyticus ssp. gallolyticus evaluated, the adjusted potential major error was considered random, and performance is acceptable. ## 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 ≥30% 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 5. Trending for Streptococcus spp. with Meropenem 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 | | --- | --- | --- | --- | --- | --- | --- | --- | | VITEK 2/Auto | S. pneumoniae | 112 | 52 (46.4) | 55 | 5 (4.5) | -42% (-52%, -31%) | Yes | | | S. agalactiae | 3 | 3 (100) | 0 | 0 (0) | -100% (-100%, -21%) | Yes | | | S. canis | 0 | 0 (0) | 0 | 0 (0) | 0 | NA | | | S. dysgalactiae ssp. 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 | 68 | 44 (64.7) | 20 | 4 (5.9) | -59% (-70%, -44%) | Yes | | VITEK 2/ Manual | S. pneumoniae | 38 | 15 (39.5) | 20 | 3 (7.9) | -32% (-48%, -13%) | Yes | | | S. agalactiae | 0 | 0 (0) | 0 | 0 (0) | 0 | NA | K260283 - Page 15 of 17 {15} | | Organism | Total Evaluable for Trending | ≥ 1 Dilution lower No. (%) | Exact No. (%) | ≥ 1 Dilution Higher No. (%) | Percent Difference (CI) | Trending Noted | | --- | --- | --- | --- | --- | --- | --- | --- | | | S. pyogenes | 0 | 0 (0) | 0 | 0 (0) | 0 | NA | | | Streptococcus spp. Viridans Group | 14 | 8 (57.1) | 6 | 0 (0) | -57% (-79%, -24%) | Yes | | VITEK 2 Compact | S. pneumoniae | 38 | 15 (39.5) | 20 | 3 (7.9) | -32% (-48%, -13%) | Yes | | | S. agalactiae | 0 | 0 (0) | 0 | 0 (0) | 0 | NA | | | S. pyogenes | 0 | 0 (0) | 0 | 0 (0) | 0 | NA | | | Streptococcus spp. Viridans Group | 14 | 5 (35.7) | 9 | 0 (0) | -36% (-61%, -7%) | Yes | | VITEK COMPACT PRO | S. pneumoniae | 38 | 13 (34.2) | 18 | 7 (18.4) | -16% (-34%, 4%) | No | | | S. agalactiae | 0 | 0 (0) | 0 | 0 (0) | 0 | NA | | | S. pyogenes | 0 | 0 (0) | 0 | 0 (0) | 0 | NA | | | Streptococcus spp. Viridans Group | 15 | 4 (26.7) | 9 | 2 (13.3) | -13% (-40%, 16%) | No | NA: Not applicable A trend toward lower MIC values was observed for S. pneumoniae (VITEK 2/auto, VITEK 2/manual, VITEK 2 Compact), S. agalactiae (VITEK 2/auto) and Streptococcus spp. Viridans Group (VITEK 2/auto, VITEK 2/manual, VITEK 2 Compact) when compared to the CLSI broth microdilution reference method, as summarized in Table 5. The following statement is included as a footnote to the performance table in the device labeling to address the observed trending: VITEK 2 Meropenem MIC values tended to be in exact agreement or at least one doubling dilution lower when testing Streptococcus pneumoniae, Streptococcus agalactiae and Streptococcus spp. Viridans Group compared to the CLSI reference broth microdilution method. ### 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: K260283 - Page 16 of 17 {16} 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 6. FDA-Approved or Recognized Interpretive Criteria | Organism | Minimum Inhibitory Concentrations (μg/mL)^{a} | | | | --- | --- | --- | --- | | | Susceptible | Intermediate | Resistant | | *Streptococcus pneumoniae* | ≤ 0.25 | 0.5 | ≥ 1 | | *Streptococcus* spp. β-Hemolytic Group | ≤0.5 | - | - | | *Streptococcus* spp. Viridans Group | ≤0.5 | - | - | $^{a}$According 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. K260283 - Page 17 of 17