VITEK 2 AST-Gram Negative Imipenem/Relebactam (<0.25/4 - >16/4 ug/ML)

{0} FDA U.S. FOOD &amp; DRUG ADMINISTRATION # 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY ASSAY ONLY ## I Background Information: A 510(k) Number K211136 B Applicant bioMérieux, Inc C Proprietary and Established Names VITEK 2 AST-Gram Negative Imipenem/Relebactam (&lt;0.25/4 - &gt;16/4 µg/mL) D Regulatory Information | Product Code(s) | Classification | Regulation Section | Panel | | --- | --- | --- | --- | | LON, LTW, LTT | Class II | 21 CFR 866.1645 - Fully Automated Short-Term Incubation Cycle Antimicrobial Susceptibility System | MI - Microbiology | ## II Submission/Device Overview: A Purpose for Submission: To modify the indications for use for imipenem/relebactam to include a new indicated species, Acinetobacter calcoaceticus-baumannii complex. B Measurand: Imipenem/Relebactam (≤0.25/4 - ≥16/4 µg/mL) C Type of Test: Automated quantitative or qualitative antimicrobial susceptibility test Food and Drug Administration 10903 New Hampshire Avenue Silver Spring, MD 20993-0002 www.fda.gov {1} K211136 - Page 2 of 10 # III Intended Use/Indications for Use: ## A Intended Use(s): See Indications for Use below. ## B Indication(s) for Use: VITEK8 2 AST-Gram Negative Imipenem/Relebactam 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 Imipenem/Relebactam is a quantitative test. Imipenim/Relebactam 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: - Acinetobacter calcoaceticus-baumannii complex - Klebsiella (Enterobacter) aerogenes - Enterobacter cloacae - Escherichia coli - Klebsiella pneumoniae - Pseudomonas aeruginosa - Citrobacter freundii - Klebsiella oxytoca In vitro data are available. but clinical significance is unknown: - Citrobacter koseri - Enterobacter asburiae 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 Limitation: Perform and alternative method of testing prior to reorting or results for the following antibiotic/organism combination(s): Imipenem/Relebactam: Serratia marcescens ## D Special Instrument Requirements: VITEK 2 and VITEK 2 Compact Systems using VITEK 2 Systems 9.03 software # IV Device/System Characteristics: ## A Device Description: The VITEK 2 AST card is a miniaturized, abbreviated and automated version of the doubling dilution technique for determining the minimum inhibitory concentration (MIC). Each VITEK 2 AST card contains 64 wells. A control well(s) which contain only nutrient medium is resident on all cards. The remaining wells contain premeasured portions of antimicrobials combined with the {2} 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-Gram Negative Imipenem/Relebactam has the following concentrations of imipenem/relebactam in the card: 0.25/4, 1/4, 4/4, and 16/4 µg/mL (equivalent standard method concentration by efficacy in µg/mL); the content of relebactam is fixed at 4 µg/mL in each dilution. The imipenem/relebactam MIC result range for the VITEK 2 is ≤0.25/4 to ≥16/4 µg/mL. For Acinetobacter calcoaceticus-baumannii complex, the VITEK 2 system is capable of reporting the following MIC results: ≤0.25/4, 0.5/4, 1/4, 2/4, 4/4, 8/4 and ≥16/4 µg/mL for the AST-Gram Negative Imipenem/relebactam test. ## B Principle of Operation: The VITEK 2 and VITEK 2 Compact Systems utilize automated growth-based detection using attenuation of light measured by an optical scanner. The optics in the systems use visible light to directly measure organism growth within each of the 64 micro-wells. Transmittance optics is based on an initial light reading of a well before significant growth has begun. Every 15 minutes throughout the incubation cycle (defined period of time based on the VITEK 2 card), light transmittance readings of each well determine organism growth by the amount of light that is prevented from passing through the well. At the completion of the incubation period, the MIC values and their associated interpretive category results for each antimicrobial on the test card are displayed in an automatically generated report. ## V Substantial Equivalence Information: ## A Predicate Device Name(s): VITEK 2 AST-Gram Negative Imipenem/Relebactam (&lt;=0.25/4 - &gt;=16/4 µg/mL) ## B Predicate 510(k) Number(s): K193572 ## C Comparison with Predicate(s): K211136 - Page 3 of 10 {3} K211136 - Page 4 of 10 | Device & Predicate Device(s): | Device K211136 | Predicate K193572 | | --- | --- | --- | | Device Trade Name | VITEK 2 AST-Gram Negative Imipenem/Relebactam | VITEK 2 AST-Gram Negative Imipenem/Relebactam | | 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. | Same | | Test Method | Automated quantitative antimicrobial susceptibility test for use with the VITEK 2 and VITEK 2 Compact Systems to determine the in vitro susceptibility of Gram-negative organisms | Same | | Inoculum | Standardized saline suspension of test organism | Same | | Antimicrobial Agent | Imipenem/relebactam | Same | | Incubation | 35 °C; 16-24 hours | Same | | Test Card | VITEK 2 Gram Negative Susceptibility Test Card | Same | | Instrument | VITEK 2 and VITEK 2 Compact | Same | | Analysis Algorithm | Growth pattern analysis | Same | | Antimicrobial Concentration | 0.25/4, 1/4, 4/4 and 16/4 μg/mL | Same | | Reporting Range | ≤0.25/4 to ≥16/4 μg/mL | Same | {4} | General Device Characteristic Differences | | | | --- | --- | --- | | Indicated organisms | C. freundii, C. koseri, E. asburiae, E. cloacae, E. coli, K. aerogenes, K. oxytoca, K. pneumoniae, P. aeruginosa, Acinetobacter calcoaceticus-baumannii complex | C. freundii, C. koseri, E. asburiae, E. cloacae, E. coli, K. aerogenes, K. oxytoca, K. pneumoniae, P. aeruginosa | VI Standards/Guidance Documents Referenced: FDA Class II Special Controls Guidance Document: Antimicrobial Susceptibility Test (AST) Systems; Guidance for Industry and FDA. Issued August 28, 2009 CLSI M07, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically, 11th ed. 2018 CLSI M100, Performance Standards for Antimicrobial Susceptibility Testing, 29th ed. 2019 CLSI M100, Performance Standards for Antimicrobial Susceptibility Testing, 30th ed. 2020 VII Performance Characteristics: A Analytical Performance: 1. Precision/Reproducibility: No new reproducibility study was needed since there was no change in the design of the device. All data previously evaluated during review of K193572 was acceptable. Reproducibility testing for the VITEK 2 AST-Gram Negative Imipenem/Relebactam was performed in support of clearance of K193572 with a 10-isolate panel composed of species indicated in the drug label. Testing was performed at three external sites. Reproducibility was evaluated for both of the VITEK 2 inoculation options and for the VITEK 2 Compact. 2. Linearity: Not Applicable 3. Analytical Specificity/Interference: Not Applicable 4. Assay Reportable Range: Not Applicable K211136 - Page 5 of 10 {5} 5. Traceability, Stability, Expected Values (Controls, Calibrators, or Methods): Testing of Acinetobacter calcoaceticus-baumannii complex isolates with the VITEK 2 AST-Gram Negative Imipenem/Relebactam took place at the time of testing Enterobacterales and $P_{\cdot}$ aeruginosa isolates in support of clearance of K193572. The QC results were acceptable. At the time of testing for K193572, the CLSI recommended QC strains, $K$ pneumoniae ATCC BAA-1705 and $K$ pneumoniae ATCC BAA-2814 were tested a sufficient number of times (at least 20 times/site) using both the VITEK 2 card and the broth microdilution (BMD) reference method. Because of the device design, the acceptable MIC ranges for CLSI-recommended QC strains were partially off-scale. Therefore, there was a need to validate a new QC strain to satisfy the QC requirements. The sponsor conducted a study to validate a novel $P$ aeruginosa strain (bioMérieux strain 105617) for use as an on-scale QC strain for imipenem/relebactam. The strain subsequently was submitted to ATCC and is cataloged as $P$ aeruginosa ATCC BAA-3144. Testing with this strain under K193572 provided results within the expected QC range for $&gt;95\%$ of tests. Subsequent to the clearance of K193572, the expected QC range for the CLSI-recommended strain $K$ pneumoniae ATCC BAA-2814 was modified from a range of $0.06 / 4 - 0.25 / 4$ $\mu \mathrm{g} / \mathrm{mL}$ to a range of $0.06 - 0.5 / 4\mu \mathrm{g} / \mathrm{mL}$ (change first implemented in CLSI document M100 $30^{\mathrm{th}}$ Edition). The results obtained with this QC strain during testing for K193572 reanalyzed using the revised expected QC range are shown in Table 1 below. Table 1. Results of QC Testing with the Revised QC Range for $K$ . pneumoniae ATCC BAA-2814 ${}^{a}$ | Organism | Conc. (μg/mL) | VITEK 2 | | | | VITEK 2 Compact | | | --- | --- | --- | --- | --- | --- | --- | --- | | | | Auto-Dilution | | Manual Dilution | | Manual Dilution | | | | | Reference | Test | Reference | Test | Reference | Test | | K. pneumoniae ATCC BAA-2814 Expected Range 0.06-0.5 μg/mL | ≤0.008 | - | NAb | - | NAb | - | NAb | | | 0.03 | - | NA | - | NA | - | NA | | | 0.06 | 6 | NA | 4 | NA | 4 | NA | | | 0.12 | 92 | NA | 70 | NA | 70 | NA | | | 0.25 | 18 | NA | 14 | NA | 14 | NA | | | ≤0.25b | - | 120 | - | 88 | - | 89 | | | 0.5 | 5 | - | 4 | - | 4 | - | | | 1 | 1 | - | 1 | - | 1 | - | | | ≥2 | - | - | - | - | - | - | ${}^{a}$ Data from K193572 reanalyzed with the revised expected QC range b The lowest concentration of imipenem/relebactam on the VITEK 2 card is $0.25 / 4\mu \mathrm{g} / \mathrm{mL}$ . Obtaining this value was considered an indicator that the quality control test results were acceptable. The sponsor included a footnote to the Quality Control table indicating that the VITEK 2 AST-Gram Negative Imipenem/Relebactam panel does not include the full CLSI-recommended dilution range for QC testing with this organism. Integrity Check: In support of clearance of K193572 $K$ . pneumoniae ATCC BAA-1705 was tested with imipenem alone as in integrity check for the plasmid encoding the $\beta$ -lactamase gene. K211136 - Page 6 of 10 {6} Inoculum Density. The DensiCHECK Plus was used for the preparation of inoculum and the instrument was standardized daily. All recorded calibration values were within acceptable parameters. Purity Checks. Purity checks were performed on all isolates tested. Only results from pure cultures were evaluated. Growth Failure. There were no instances of growth failure during the evaluation of imipenem/relebactam. 6. Detection Limit: Not Applicable 7. Assay Cut-Off: Not Applicable ## B Comparison Studies: 1. Method Comparison with Predicate Device: Testing of imipenem/relebactam with isolates belonging to the Acinetobacter calcoaceticus-baumannii complex was performed at three external sites and one internal site. Results obtained with VITEK 2 AST-Gram Negative Imipenem/Relebactam were compared to results obtained with the CLSI broth microdilution reference panel. The MIC result range for the VITEK 2 AST-Gram Negative Imipenem/Relebactam is ≤0.25/4 to ≥16/4 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°C, 16 to 24 hours The VITEK 2 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 32 clinical isolates of Acinetobacter calcoaceticus-baumannii complex were evaluated: 9 isolates (28.1%) were considered contemporary isolates and 23 (71.9%) were stock isolates. Isolates included: Acinetobacter baumannii (20 isolates), and Acinetobacter baumannii complex (12 isolates). In addition, 24 challenge isolates of Acinetobacter calcoaceticus-baumannii complex were evaluated. Isolates included: Acinetobacter baumannii (10 isolates), Acinetobacter baumannii complex (13 isolates) and Acinetobacter calcoaceticus (1 isolate). For Acinetobacter calcoaceticus-baumannii complex evaluated using VITEK 2 and autodilution, the combined clinical and challenge EA and CA were acceptable at 98.2% with all errors being minor (i.e. no major or very major errors). A total of 35 resistant strains were evaluated demonstrating the ability of the assay to detect resistance in this complex. (Table 2) K211136 - Page 7 of 10 {7} Table 2. AutoDilution: Performance of Acinetobacter calcoaceticus-baumannii Complex | | Tot | EA N | EA % | Eval Tot | Eval EA N | Eval EA % | CA Tot | CA % | No. R | No. S | min | maj | vmj | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Acinetobacter calcoaceticus-baumannii Complexa | | | | | | | | | | | | | | | Clinical | 32 | 31 | 96.9 | 2 | 1 | 50.0 | 32 | 100 | 19 | 13 | 0 | 0 | 0 | | Challenge | 24 | 24 | 100 | 8 | 8 | 100 | 23 | 95.8 | 16 | 8 | 1 | 0 | 0 | | Total | 56 | 55 | 98.2 | 10 | 9 | 90.0 | 55 | 98.2 | 35 | 21 | 1 | 0 | 0 | a Includes A. baumannii, A. baumannii complex and A. calcoaceticus EA - Essential Agreement CA - Category Agreement EVAL - Evaluable Isolates R - Resistant Isolates min - minor errors maj - major errors vmj - very major errors S - Susceptible Isolates Essential agreement (EA) occurs when the result of the reference method and that of the VITEK 2 AST-Gram Negative imipenem/relebactam 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 imipenem/relebactam. Category agreement (CA) occurs when the interpretation of the result of the reference method agrees exactly with the interpretation provided by VITEK 2 AST-Gram Negative Meropenem For Acinetobacter calcoaceticus-baumannii complex evaluated using manual dilution with VITEK 2 and VITEK 2 Compact, EA and CA were acceptable at $100\%$ with no major, very major or minor errors. (Table 3). Table 3. Manual Dilution: Performance of Acinetobacter calcoaceticus-baumannii Complex | | Tot | EA N | EA % | Eval Tot | Eval EA N | Eval EA % | CA Tot | CA % | No. R | No. S | min | maj | vmj | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Acinetobacter calcoaceticus-baumannii Complexa | | | | | | | | | | | | | | | VITEK 2 | 24 | 24 | 100 | 8 | 8 | 100 | 24 | 100 | 16 | 8 | 0 | 0 | 0 | | Compact | 24 | 24 | 100 | 8 | 8 | 100 | 24 | 100 | 16 | 8 | 0 | 0 | 0 | a Includes A. baumannii, A. baumannii complex and A. calcoaceticus The performance of VITEK 2 AST-Gram Negative Imipenem/Relebactam with Acinetobacter calcoaceticus-baumannii complex using both autodilution (VITEK 2) and manual dilution (VITEK 2 and VITEK 2 Compact) is acceptable. Subsequent to clearance of K193572, the imipenem/relebactam drug label was revised to include S. marcescens as a species for which the drug was shown to have in vitro and clinical activity. Testing of S. marcescens showed low performance on VITEK 2 systems. To address testing with this drug/organism combination the sponsor included the following limitation in the device labeling: Perform and alternative method of testing prior to reporting or results for the following antibiotic/organism combination(s): Imipenem/Relebactam: Serratia marcescens K211136 - Page 8 of 10 {8} # MIC Trending A trending analysis was conducted using the combined data (clinical and challenge) obtained from the VITEK 2 auto-dilution method for each organism group. 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. Results that are not clearly at least one dilution lower, at least one dilution higher or in exact agreement with the CLSI reference method are not considered in the trending analysis. Organism groups for which the difference between the percentage of isolates with higher vs. lower readings was &gt; 30% and for which the confidence interval was determined to be statistically significant were considered to show evidence of trending. Trending that showed higher or lower MIC values compared to the reference is addressed in the labeling. Evaluation of results for *Acinetobacter calcoaceticus-baumannii* Complex using autodilution on VITEK 2 showed that a majority of isolates provided MICs were not evaluable for trending due to the majority of the data being off-scale; however, the few evaluable results indicate a trend toward lower MIC results with the limited number of isolates available for trending analysis. (Table 4). Table 4. Trending Observed for *Acinetobacter calcoaceticus-baumannii* complex | Organism | Total Evaluable for Trending | ≥1 Dilution lower No. (%) | Exact No. (%) | ≥1 Dilution Higher No. (%) | Percent Difference (CI) | Trending Noted | | --- | --- | --- | --- | --- | --- | --- | | *Acinetobacter calcoaceticus-baumannii complex*. | 15 | 10 (66.7) | 5 (33.3) | 0 | -66.7 (-84.8 to -34.4) | Yes | The sponsor added the trending results for *Acinetobacter calcoaceticus-baumannii* complex to the current trending footnote to the performance table in the device labeling (additions for *Acinetobacter calcoaceticus-baumannii complex* in bold font): A trending analysis was conducted using combined data (clinical and challenge) for *Enterobacteriaceae* and *Pseudomonas aeruginosa* and *Acinetobacter calcoaceticus-baumannii complex*. This trending analysis determined the VITEK 2 Imipenem/Relebactam, when compared to the reference broth microdilution, tended to be at least one doubling dilution lower for *Citrobacter koseri*, *Acinetobacter calcoaceticus-baumannii complex* and *Klebsiella pneumoniae*, and at least one doubling dilution higher for *Enterobacter cloacae*. 2. Matrix Comparison: Not applicable C Clinical Studies: 1. Clinical Sensitivity: Not Applicable K211136 - Page 9 of 10 {9} 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: Table 5. FDA-Identified Interpretive Criteria for Imipenem/Relebactamᵃ | Organism | Interpretive Criteria for Imipenem/Relebactam (μg/mL) | | | | --- | --- | --- | --- | | | Susceptible | Intermediate | Resistant | | Enterobacterales | ≤1/4 | 2/4 | ≥4/4 | | P. aeruginosa | ≤2/4 | 4/4 | ≥8/4 | | Acinetobacter calcoaceticus-baumannii complex | ≤2/4 | 4/4 | ≥8/4 | ᵃ FDA STIC Webpage 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. 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 AST-GN Imipenem/relebactam when revised breakpoints for imipenem/relebactam 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 imipenem/relebactam 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. K211136 - Page 10 of 10