VITEK 2 AST-GN Amikacin (<=1 ->=64 ug/mL)

{0} Page 1 of 13 # 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY ASSAY ONLY TEMPLATE A. 510(k) Number: K172731 B. Purpose for Submission: To obtain a substantial equivalence determination for Amikacin for testing of gram negative bacilli on the VITEK 2 and VITEK 2 Compact Antimicrobial Susceptibility Test (AST) Systems C. Measurand: The VITEK 2 AST-Gram Negative card contains the following concentrations of Amikacin: 2, 4, 16, and 48 µg/mL (equivalent standard method concentration by efficacy in µg/mL). The Amikacin MIC reporting range for the card is ≤ 1 – ≥ 64 µg/mL for all organisms except *Acinetobacter* species. The calling range for *Acinetobacter* species is ≤ 2 – ≥ 64 µg/mL. D. Type of Test: Automated quantitative or qualitative antimicrobial susceptibility test for Amikacin E. Applicant: bioMérieux, Inc. F. Proprietary and Established Names: VITEK 2 AST-Gram Negative Amikacin (≤ 1 – ≥ 64 µg/mL) G. Regulatory Information: 1. Regulation section: 21 CFR 866.1645: Fully Automated Short-Term Incubation Cycle Antimicrobial Susceptibility System 2. Classification: Class II {1} Page 2 of 13 3. Product code(s): LON – Fully automated short-term incubation cycle antimicrobial susceptibility system LTW – Susceptibility Test Cards, Antimicrobial LTT – Panels, Test, Susceptibility, Antimicrobial 4. Panel: Microbiology (83) H. Intended Use/Indications for Use: 1. Intended Use (s): The VITEK 2 Antimicrobial Susceptibility Test (AST) is intended to be used with the VITEK 2 Systems for the automated quantitative or qualitative susceptibility testing of isolated colonies for the most clinically significant aerobic gram-negative bacilli, *Staphylococcus* spp., *Enterococcus* spp., *Streptococcus* spp. and clinically significant yeast. 2. Indications for Use: VITEK 2 AST-Gram Negative Amikacin 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 Amikacin is a quantitative test. Amikacin 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: - *Pseudomonas* species - *Escherichia coli* - *Proteus mirabilis* - *Klebsiella* species - *Enterobacter* species - *Serratia* species - *Acinetobacter* species (excluding *A. baumannii* Complex) In vitro data available but clinical significance unknown: - *Citrobacter freundii* The VITEK 2 Antimicrobial Susceptibility Test (AST) is intended to be used with the VITEK 2 Systems for the automated quantitative or qualitative susceptibility testing of isolated colonies for the most clinically significant aerobic gram-negative bacilli, *Staphylococcus* spp., *Enterococcus* spp., *Streptococcus* spp. and clinically significant yeast. {2} Page 3 of 13 3. Special conditions for use statement(s): For Prescription Use Only Limitations: 1. "Perform an alternative method of testing prior to reporting of results for the following antibiotic/organism combination(s): Amikacin: Acinetobacter baumannii complex" 2. "The ability of the AST card to detect resistance with the following combination(s) is unknown because resistant strains were either not available or an insufficient number were encountered at the time of comparative testing: Amikacin: Pseudomonas species, Escherichia coli, Proteus mirabilis, Klebsiella species, Enterobacter species, Serratia species, Citrobacter freundii" 4. Special instrument requirements: VITEK 2 and VITEK 2 Compact Systems using VITEK 2 Systems 8.01 software I. Device Description: The VITEK 2 AST card utilizes a miniaturized, abbreviated, and automated version of the doubling dilution technique for determining the minimal inhibitory concentration (MIC) on the VITEK 2 and VITEK 2 Compact Systems. Each VITEK 2 AST card has 64 microwells containing dehydrated media with or without an antimicrobial. A control well that contains only dehydrated culture medium is resident on all cards, with the remaining wells containing premeasured dried amounts of a specific antibiotic combined with culture medium. VITEK 2 AST-GN Amikacin has 2, 4, 16, and 48 µg/mL concentrations included in the test. The dried media in the card is rehydrated with the organism suspension during the vacuum filling process and is then sealed. The VITEK 2 System has two options for preparing the AST card inoculum including an auto-dilution or manual dilution method. The inoculated, sealed card is automatically loaded into the carousel of the instrument and incubated (35.5°C) for the duration of the test. In contrast, the VITEK 2 Compact instrument has a manual inoculation and sealing operation. Growth of the test organism is optically monitored and measured four times per hour throughout the incubation cycle (up to 18 hours for GN cards). Interpretive calls are calculated by the instrument once a predefined growth threshold is obtained. When the test is complete, the VITEK 2 card is automatically ejected from the carousel into a waste container. A report is generated that contains the minimal inhibitory concentration (MIC) value with an interpretation category of susceptible, intermediate, or resistant for each antimicrobial on the card. The MIC result reporting range for Amikacin on the VITEK 2 AST-GN card is ≤ 1 – ≥ 64 µg/mL for Enterobacteriaceae and Pseudomonas species {3} and $\leq 2 - \geq 64~\mu \mathrm{g / mL}$ for Acinetobacter species. # J. Substantial Equivalence Information: 1. Predicate device name(s): VITEK 2 AST-GN Cefepime 2. Predicate $510(\mathrm{k})$ number(s): K161227 3. Comparison with predicate: | Similarities | | | | --- | --- | --- | | Item | Device: VITEK 2 AST-GN Amikacin (K172731) | Predicate Device: VITEK 2 AST-GN Cefepime (K161227) | | Intended Use | The VITEK 2 Antimicrobial Susceptibility Test (AST) is intended to be used with the VITEK 2 Systems for the automated quantitative or qualitative susceptibility testing of isolated colonies for the most clinically significant aerobic gram-negative bacilli, Staphylococcus spp., Enterococcus spp., Streptococcus spp. and clinically significant yeast. | 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 bacilli | Same | | Inoculum | Standardized saline suspension of test organism | Same | | Test Card | VITEK 2 Gram Negative Susceptibility Test Card | Same | | Instrument | VITEK 2 and VITEK 2 Compact Systems | Same | | Analysis Algorithm | Growth pattern analysis | Same | | Detection Method | Light optics using optical scanner | Same | | Report | Automatically generated and contains the MIC value with an interpretive category (S, I, R) for each antimicrobial on the test card | Same | {4} | Differences | | | | --- | --- | --- | | Item | Device: VITEK 2 AST-GN Amikacin (K172731) | Predicate Device: VITEK 2 AST-GN Cefepime (K161227) | | Antimicrobial Agent | Amikacin | Cefepime | | Antimicrobial Concentrations | 2, 4, 16, 48 μg/mL | 0.25, 1, 4, 16, 32 μg/mL | | Reporting Range | Enterobacteriaceae, Pseudomonas species ≤ 1 - ≥ 64 μg/mL Acinetobacter species ≤ 2 - ≥ 64 μg/mL | Enterobacteriaceae, P. aeruginosa ≤0.12 - ≥32 μg/mL | | Analysis Algorithm | Unique to Amikacin | Unique to Cefepime | ## K. Standard/Guidance Document Referenced (if applicable) - 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; Approved Standard-Ninth Edition” Vol. 32 No. 2 (January 2012) - CLSI M100-S24, “Performance Standards for Antimicrobial Susceptibility Testing”; Twenty-fourth Informational Supplement, Vol. 33 No. 1 (January 2014) ## L. Test Principle: The VITEK 2 and VITEK 2 Compact Systems utilize automated growth-based detection using attenuation of light measured by an optical scanner. The optics within the systems use visible light to directly measure organism growth within each of the 64 microwells. Transmittance optics are 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 measures 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. ## M. Performance Characteristics (if/when applicable): ### 1. Analytical performance: #### a. Precision/Reproducibility: A reproducibility study for the VITEK 2 AST-GN card with Amikacin was conducted at three clinical sites using ten isolates of Gram-negative bacilli consistent with the Page 5 of 13 {5} Intended Use. Testing was performed on three separate days and in triplicate for a total of 270 data points. The ten isolates tested in the reproducibility study included Serratia marcescens (one isolate), Pseudomonas aeruginosa (one isolate), Escherichia coli (two isolates), Proteus mirabilis (one isolate), Enterobacter aerogenes (one isolate), Providencia stuartii (one isolate), Klebsiella pneumoniae pneumoniae (one isolate), and Enterobacter cloacae complex (two isolates). Inocula were prepared using both the auto-dilution and manual dilution methods for testing in the VITEK 2 System. Inocula were prepared by the manual dilution method only for use with the VITEK 2 Compact. The mode MIC value was determined and the reproducibility was calculated based on MIC values that fell within +/- one doubling dilution from the mode MIC value. Both intra-site and inter-site reproducibility for Amikacin was calculated. There were no off-scale MIC results for any inoculum preparation method for both the VITEK 2 or VITEK 2 Compact. Reproducibility was calculated per the AST Special Controls Guidance. An overall reproducibility of 100% was obtained for the VITEK 2 auto-dilution method, the VITEK 2 manual dilution method, and the VITEK 2 Compact manual dilution method. When combined across all three sites, reproducibility results were acceptable. b. Linearity/assay reportable range: Not applicable c. Traceability, Stability, Expected values (controls, calibrators, or methods): Inoculum Density Control The DensiCHEK™ Plus was used to standardize the inoculum to a 0.5 MacFarland 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. Growth Failure Rate Of 473 clinical isolates that were evaluated, two isolates did not grow in the VITEK 2 Amikacin test using the VITEK 2 System. Complete test results were available for 471 clinical isolates (344 Enterobacteriaceae, 49 Non-Enterobacteriaceae, and 78 Pseudomonas species). The growth failure rate was 0.4% and was acceptable. All 95 challenge organisms grew in the VITEK 2 GN card with Amikacin using both the auto-dilution and manual dilution methods of the VITEK 2 and Compact Systems. Therefore, 566 isolates had VITEK 2 AST results available. Page 6 of 13 {6} # Quality Control (QC) Testing Two FDA/CLSI recommended QC organisms were tested throughout the comparative testing at three study sites. The organisms tested were Escherichia coli ATCC 25922 and Pseudomonas aeruginosa ATCC 27853. These recommended QC organisms were tested a minimum of 20 times/site by both the VITEK 2 AST-GN card with Amikacin and with the CLSI broth microdilution reference method. Both the auto-dilution and the manual dilution methods were within the expected range $&gt;95\%$ of the time. In instances where any organism was out of range for the reference method, all testing data from that particular day was invalid and repeated. The following table (Table 1) provides a summary of QC results. Table 1. Quality Control Results Summary for VITEK 2 (Auto-Dilution and Manual Dilution Methods) and VITEK 2 Compact (Manual Dilution Method) | | | VITEK 2 Auto-Dilution | | VITEK 2 Manual Dilution | | VITEK 2 Compact Manual Dilution | | | --- | --- | --- | --- | --- | --- | --- | --- | | Organism | Conc. (μg/mL) | Test | Reference | Test | Reference | Test | Reference | | E. coli ATCC 25922 Expected Range 0.5 – 4 μg/mL | ≤0.25 | | | | | | | | | 0.5 | | | | | | | | | ≤1* | | 54 | | 28 | | 28 | | | 2 | 231 | 265 | 106 | 160 | 109 | 160 | | | 4 | 114 | 26 | 99 | 17 | 96 | 17 | | | 8 | | | | | | | | | 16 | | | | | | | | | 32 | | | | | | | | | 64 | | | | | | | | | ≥128 | | | | | | | | | | | | | | | | | P. aeruginosa ATCC 27853 Expected Range 1 – 4 μg/mL | ≤0.25 | | | | | | | | | 0.5 | | | | | | | | | ≤1* | | 7 | | 6 | | 6 | | | 2 | 201 | 305 | 125 | 183 | 114 | 182 | | | 4 | 138 | 28 | 75 | 11 | 85 | 11 | | | 8 | 1 | | | | | | | | 16 | | | | | | | | | 32 | | | | | | | | | 64 | | | | | | | | | ≥128 | | | | | | | *The lowest dilution of the VITEK 2 Amikacin MIC range is $\leq 1\mu \mathrm{g / mL}$ The expected range for $E.$ coli ATCC 25922 with Amikacin is $0.5 - 4\mu \mathrm{g / mL}$ . Even though the Amikacin concentrations included in the VITEK 2 AST-GN card are 2, 4, 16, and $48~\mu \mathrm{g / mL}$ , the reporting range is $\leq 1 - \geq 64~\mu \mathrm{g / mL}$ for Enterobacteriaceae and Pseudomonas species. All results for $E.$ coli ATCC 25922 and $P.$ aeruginosa ATCC 27853 were on scale (i.e., at 2 or $4\mu \mathrm{g / mL}$ ) for the VITEK 2 (both automatic and manual dilutions) and VITEK 2 Compact Systems even though both VITEK systems {7} report the lowest end of the scale as ≤1 μg/mL. Overall, performance of the QC organisms was found to be acceptable. d. Detection limit: Not applicable e. Analytical Specificity: Not applicable f. Assay cut-off: Not applicable 2. Comparison studies: a. Method comparison with predicate device: Results obtained with the bioMérieux VITEK 2 AST-Gram Negative card with Amikacin were compared to results obtained with the CLSI broth microdilution reference panel. The following concentrations of Amikacin are contained in the VITEK 2 AST-GN test card: 2, 4, 16, and 48 μg/mL (equivalent standard method concentration by efficacy in μg/mL) and the reporting range is ≤ 1 – ≥ 64 μg/mL (i.e., ≤ 1, 2, 4, 8, 16, 32, ≥ 64). Reference panels containing two-fold serial dilutions ranging from 0.25 to 256 μg/mL were inoculated as outlined in the CLSI document M07-A9. All test inocula used for the evaluation of VITEK 2 AST-GN Amikacin and the reference method were standardized using the DensiCHEK™ Plus instrument. The cards were inoculated with each test organism by auto-dilution for reading by the VITEK 2 System and by manual dilution for reading on the VITEK 2 System and Compact instrument. The VITEK 2 Amikacin susceptibility test was evaluated by six independent clinical sites located in different geographic regions of the United States. A total of 473 clinical isolates were tested on the VITEK 2 Amikacin test; however, only 471 isolates grew (344 Enterobacteriaceae, 49 non-Enterobacteriaceae, and 78 Pseudomonas species). Every clinical isolate was tested once by auto-dilution on the VITEK 2 System and the reference method using the same initial standardized suspension. The majority of clinical isolates were isolated from fresh clinical specimens (318 isolates; 67.2%) and 155 were stock isolates (32.8%). A total of 95 challenge organisms (75 Enterobacteriaceae, 2 non-Enterobacteriaceae (Acinetobacter spp.), and 18 Pseudomonas spp.) were evaluated at one external site. The challenge set was tested with both the auto-dilution and manual dilution options Page 8 of 13 {8} of the VITEK 2 System and with the manual dilution method on the VITEK 2 Compact System. The study evaluated 471 clinical isolates and 95 challenge isolates for a combined data set of 566 isolates with AST results (419 Enterobacteriaceae, 25 Acinetobacter species, 26 other non-Enterobacteriaceae, 96 Pseudomonas species). The combined performance (clinical and challenge isolates) of the VITEK 2 Amikacin test as compared to the reference method is shown in Table 2 for 566 isolates. Of the 566 total organisms evaluated in the comparative analysis, 79 clinical organisms were not indicated in the FDA drug label for Amikacin ( $\sim 14\%$ ). When the non-indicated organisms were removed from the clinical performance evaluation, the EA and CA were slightly higher at $95.9\%$ and $99.0\%$ , respectively compared to $94.9\%$ EA and $98.4\%$ CA with the non-indicated organisms included. Because overall performance of the VITEK 2 AST-GN card with Amikacin was not affected, incorporation of the 79 non-indicated organisms was acceptable. Table 2. Performance ${}^{ \ddagger }$ of Clinical and Challenge Isolates, VITEK 2 Auto-Dilution Method | Organism Group | EA Total | EA N | EA % | Eval EA Total | Eval EA N | Eval EA % | CA N | CA % | #R | Min | Maj | Vmj | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Enterobacteriaceae | | | | | | | | | | | | | | Clinical | 344 | 326 | 94.8 | 243 | 225 | 92.6 | 344 | 100.0 | 0 | 0 | 0 | 0 | | Challenge | 75 | 74 | 98.7 | 46 | 45 | 97.8 | 73 | 97.3 | 1 | 2 | 0 | 0 | | Combined | 419 | 400 | 95.5 | 289 | 270 | 93.4 | 417 | 99.5 | 1 | 2 | 0 | 0 | | Acinetobacter species | | | | | | | | | | | | | | Clinical | 23 | 22 | 95.7 | 6 | 5 | 83.3 | 23 | 100.0 | 5 | 0 | 0 | 0 | | Challenge | 2 | 2 | 100.0 | 0 | 0 | - | 2 | 100.0 | 0 | 0 | 0 | 0 | | Combined | 25 | 24 | 96.0 | 6 | 5 | 83.3 | 25 | 100.0 | 5 | 0 | 0 | 0 | | Other Non-Enterobacteriaceae (excluding Acinetobacter species) | | | | | | | | | | | | | | Clinical | 26 | 23 | 88.5 | 6 | 4 | 66.7 | 22 | 84.6 | 16 | 2 | 2 | 0 | | Challenge | - | - | - | - | - | - | - | - | - | - | - | - | | Combined | 26 | 23 | 88.5 | 6 | 4 | 66.7 | 22 | 84.6 | 16 | 2 | 2 | 0 | | Pseudomonas species | | | | | | | | | | | | | | Clinical | 78 | 72 | 92.3 | 70 | 64 | 91.4 | 76 | 97.4 | 0 | 2 | 0 | 0 | | Challenge | 18 | 18 | 100.0 | 13 | 13 | 100.0 | 17 | 94.4 | 3 | 1 | 0 | 0 | | Combined | 96 | 90 | 93.8 | 83 | 77 | 92.8 | 93 | 96.9 | 3 | 3 | 0 | 0 | | Enterobacteriaceae, Acinetobacter species, Other Non-Enterobacteriaceae, Pseudomonas species | | | | | | | | | | | | | | Clinical | 471 | 443 | 94.1 | 325 | 298 | 91.7 | 465 | 98.7 | 21 | 4 | 2 | 0 | | Challenge | 95 | 94 | 98.9 | 59 | 58 | 98.3 | 92 | 96.8 | 4 | 3 | 0 | 0 | | Combined | 566 | 537 | 94.9 | 384 | 356 | 92.7 | 557 | 98.4 | 25 | 7 | 2 | 0 | $^{\ddagger}$ EA - Essential Agreement (+/- 1 doubling dilution) CA - Category Agreement EVAL - Evaluable isolates R - Resistant isolates Min - Minor discrepancies Maj - Major discrepancies Vmj - Very major discrepancies Essential agreement (EA) was calculated when the VITEK 2 System results were within $+/-$ one doubling dilution of the reference method results. Category agreement (CA) was calculated when the VITEK 2 System result interpretations agreed exactly with the reference method result interpretations. Evaluable results were defined as when both the reference method results and the VITEK 2 System results were on-scale. Evaluable results were also defined as when the reference method results were on-scale and off-scale VITEK 2 System results clearly did not agree within the accepted $+/-$ one doubling dilution. {9} Enterobacteriaceae: The overall performance of Enterobacteriaceae was acceptable with 95.5% EA and 99.5% CA. There were no major or very major errors. Non-Enterobacteriaceae: The overall performance of non-Enterobacteriaceae organisms (Acinetobacter species and few non-indicated organisms) was acceptable with 92.2% EA and 92.2% CA. There were two major errors and no very major errors. Pseudomonas species: The overall performance of Pseudomonas species was acceptable with 93.8% EA and 96.9% CA. There were no major or very major errors. Overall Performance: The overall performance using the auto-dilution method of the VITEK 2 System demonstrated an EA of 94.9% and an overall CA of 98.4%. There were no very major errors, two major errors (0.4% error rate, 2/535 susceptible organisms), and 7 minor errors (1.2% error rate, 7/566 total organisms). Performance for Amikacin on the VITEK 2 card met the acceptance criteria for major error (≤3%). The performance based on combined clinical and challenge data was acceptable. ## Challenge Data – Auto and Manual Dilution The challenge set of 95 isolates (75 Enterobacteriaceae, 2 non-Enterobacteriaceae; Acinetobacter species, and 18 Pseudomonas aeruginosa) was evaluated on the VITEK 2 System using both auto and manual dilution methods and on the VITEK 2 Compact System with the manual dilution method only. All challenge data was generated at one testing site. Overall performance of the challenge data is shown in Table 3. Table 3. Performance of Challenge Isolates, VITEK 2 and VITEK 2 Compact-Manual Dilution | Organism Group | EA Total | EA N | EA % | Eval EA Total | Eval EA N | Eval EA % | CA N | CA % | #R | Min | Maj | Vmj | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | VITEK 2 System | | | | | | | | | | | | | | Auto-dilution | 95 | 94 | 98.9 | 59 | 58 | 98.3 | 92 | 96.8 | 4 | 3 | 0 | 0 | | Manual dilution | 95 | 94 | 98.9 | 62 | 61 | 98.4 | 93 | 97.9 | 4 | 2 | 0 | 0 | | VITEK 2 Compact | | | | | | | | | | | | | | Manual dilution | 95 | 93 | 97.9 | 62 | 60 | 96.8 | 92 | 96.8 | 4 | 3 | 0 | 0 | The performance of the challenge isolates using the VITEK 2 Amikacin test on both the VITEK 2 and VITEK 2 Compact Systems was acceptable. ## Resistant Organisms A total of 25 resistant isolates were identified in the combined clinical (n=21) and challenge (n=4) study of Amikacin for the VITEK 2 auto-dilution method out of 566 organisms (4.4%). However, the following indicated organisms had no resistant isolates and/or an insufficient number of resistant isolates available during Page 10 of 13 {10} comparative testing: Pseudomonas species, Escherichia coli, Proteus mirabilis, Klebsiella species, Enterobacter species, Serratia species, and Citrobacter freundii. This was addressed with the following limitation in the package insert: "The ability of the AST card to detect resistance with the following combination(s) is unknown because resistant strains were either not available or an insufficient number were encountered at the time of comparative testing: Amikacin: Pseudomonas species, Escherichia coli, Proteus mirabilis, Klebsiella species, Enterobacter species, Serratia species, Citrobacter freundii" # MIC Trends Using the combined clinical and challenge data for indicated Enterobacteriaceae organisms, an analysis of trending was conducted. This trending calculation takes into account MIC values that are determined to be $\leq 1$ or $\geq 1$ doubling dilution compared to the reference method irrespective whether the device MIC values are on-scale or not. Results of trending analyses for evaluable isolates are shown in Table 4.1 and Table 4.2 for Enterobacteriaceae and $P_{\cdot}$ aeruginosa, respectively. Table 4.1. Trending Analysis of Evaluable Enterobacteriaceae Clinical and Challenge Isolate Results, VITEK 2 Auto-Dilution Method | Amikacin ≤1 - ≥64μg/mL | # Eval Isolatesa | Difference in MIC as Compared to the CLSI Reference Method | | | | | | --- | --- | --- | --- | --- | --- | --- | | | | ≥2 dilution lower | ≥1 dilution lower | Exact | ≥1 dilution higher | ≥2 dilution higher | | C. freundii | 41 | 1 | 5 | 12 (29.27%) | 20 | 3 | | | | 6 (14.63%)b95% CI (6.88% to 28.44%) | | | 23 (56.10%)b95% CI (41.04% to 70.11%) | | | E. cloacae complex | 14 | 0 | 1 | 2 (14.29%) | 10 | 1 | | | | 1 (7.14%)c95% CI (1.27% to 31.47%) | | | 11 (78.57%)c95% CI (52.41% to 92.43%) | | | E. coli | 103 | 3 | 14 | 47 (45.63%) | 39 | 0 | | | | 17 (16.50%)d95% CI (10.57% to 24.85%) | | | 39 (37.86%)d95% CI (29.09% to 47.51%) | | | K. pneumoniae pneumoniae | 14 | 0 | 1 | 1 (7.14%) | 12 | 0 | | | | 1 (7.14%)e95% CI (1.27% to 31.47%) | | | 12 (85.71%)e95% CI (60.06% to 95.99%) | | | S. marcescens | 13 | 0 | 1 | 3 (23.08%) | 9 | 0 | | | | 1 (7.69%)f95% CI (1.37% to 33.31%) | | | 9 (69.23%)f95% CI (42.37% to 87.32%) | | a Total number of evaluable results for trending analysis b Difference: 41.46%: 95% CI (21.03% to 57.48%) c Difference: 71.43%: 95% CI (35.70% to 86.48%) d Difference: 21.36%: 95% CI (9.25% to 32.68%) e Difference: 78.57%: 95% CI (43.22% to 90.41%) f Difference: 61.54%: 95% CI (24.42% to 80.70%) {11} Table 4.2. Trending Analysis of Evaluable $P$ . aeruginosa Clinical and Challenge Isolate Results, VITEK 2 Auto-Dilution Method | Amikacin ≤1 - ≥ 64μg/mL | # Eval Isolatesa | Difference in MIC as Compared to the CLSI Reference Method | | | | | | --- | --- | --- | --- | --- | --- | --- | | | | ≥ 2 dilution lower | ≥ 1 dilution lower | Exact | ≥ 1 dilution higher | ≥ 2 dilution higher | | P. aeruginosa | 85 | 1 | 2 | 27 (31.76%) | 50 | 5 | | | | 3 (3.53%)b95% CI (1.21% to 9.87%) | | | 55 (64.71%)b95% CI (54.11% to 74.03%) | | a Total number of evaluable results for trending analysis b Difference: 61.18%: 95% CI (48.83% to 70.78%) A higher MIC reading trend was observed in the overall performance of C. freundii, E. cloacae complex, E. coli, K. pneumoniae pneumoniae, S. marcescens, and P. aeruginosa compared to CLSI broth microdilution, which raises concerns for potential major errors. To address the high trending and the potential occurrence of major error(s) for Amikacin when testing select clinical and challenge Enterobacteriaceae and Pseudomonas aeruginosa with the VITEK 2 System, the following statement was added as a footnote in the labeling (Product Information Manual): "VITEK 2 Amikacin MIC values for evaluable C. freundii, E. cloacae complex, E. coli, K. pneumoniae pneumoniae, P. aeruginosa, and S. marcescens tended to be in exact agreement or at least one doubling dilution higher compared to the CLSI reference broth microdilution." The analysis of Acinetobacter species MIC data demonstrated no notable trending. b. Matrix comparison: Not applicable 3. Clinical studies: a. Clinical sensitivity: Not applicable b. Clinical specificity: Not applicable c. Other clinical supportive data (when a. and b. are not applicable): Not applicable {12} 4. Clinical cut-off: Not applicable 5. Expected values/Reference range: Table 5. Interpretive Criteria for Amikacin (FDA Drug Label) | Organism | FDA Interpretive Criteria for Amikacin MIC (μg/mL) | | | | --- | --- | --- | --- | | | S | I | R | | Enterobacteriaceae | ≤16 | 32 | ≥64 | | Pseudomonas species | ≤16 | 32 | ≥64 | | Acinetobacter species | ≤16 | 32 | ≥64 | N. Proposed Labeling: The labeling is sufficient and it satisfies the requirements of 21 CFR Part 809.10. O. Conclusion: The submitted information in this premarket notification is complete and supports a substantial equivalence decision.