VITEK 2 GRAM NEGATIVE TRIMETHOPRIM/SULFAMETHOAZOLE

{0} 1 # 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY ASSAY ONLY TEMPLATE A. 510(k) Number: k110106 B. Purpose for Submission: To obtain a substantial equivalence determination for the addition of Trimethoprim/Sulfamethoxazole (SXT) to the VITEK® 2 and VITEK® 2 Compact Antimicrobial Susceptibility Test (AST) Systems. C. Measurand: Trimethoprim/Sulfamethoxazole concentrations of 1/19, 4/76, and 16/304 µg/mL D. Type of Test: A minimum inhibitory concentration (MIC) assay, determined using qualitative growth based detection algorithm using predetermined growth threshold. The MIC reporting result range of the card is ≤ 20 (1/19) – ≥320 (16/304) µg/mL. E. Applicant: bioMérieux, Inc. F. Proprietary and Established Names: VITEK® 2 Gram Negative SXT G. Regulatory Information: | Product Code | Classification | Regulation Section | Panel | | --- | --- | --- | --- | | LON | Class II | 21 CFR 866.1645 | Microbiology | H. Intended Use: 1. Intended use(s): VITEK® 2 Gram Negative Trimethoprim/Sulfamethoxazole is designed for antimicrobial susceptibility testing of Gram-Negative bacilli. VITEK® 2 Gram Negative Trimethoprim/Sulfamethoxazole is a qualitative test intended for use {1} with the VITEK® 2 and VITEK 2 Compact Systems as a laboratory aid in the determination of in vitro susceptibility to antimicrobial agents. Trimethoprim/Sulfamethoxazole has been shown to be active against the microorganisms listed below according to the FDA label for the antimicrobial. **Active in vitro and in clinical infections:** - Escherichia coli (including susceptible enterotoxigenic strains implicated in traveler's diarrhea) - Klebsiella species - Enterobacter species - Morganella morganii - Proteus vulgaris - Proteus mirabilis - Shigella flexneri - Shigella sonnei 2. **Indication(s) for use:** VITEK® 2 Gram Negative Trimethoprim/Sulfamethoxazole is designed for antimicrobial susceptibility testing of Gram-Negative bacilli. VITEK® 2 Gram Negative Trimethoprim/Sulfamethoxazole is a qualitative test 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. Trimethoprim/Sulfamethoxazole has been shown to be active against the microorganisms listed below according to the FDA label for the antimicrobial. **Active in vitro and in clinical infections:** - Escherichia coli (including susceptible enterotoxigenic strains implicated in traveler's diarrhea) - Klebsiella species - Enterobacter species - Morganella morganii - Proteus vulgaris - Proteus mirabilis - Shigella flexneri - Shigella sonnei 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 agalactiae, S. pneumoniae and clinically significant yeast. 2 {2} 3. Special conditions for use statement(s): Prescription use only 4. Special instrument requirements: For use with the VITEK 2 and VITEK 2 Compact Systems I. Device Description: VITEK 2 AST card containing the test is inoculated with a standardized suspension of the organism to be tested. The VITEK 2 System automatically fills, seals, and places the card into the incubator/reader while the VITEK 2 Compact System has manual filling, sealing and loading operation. The incubated card is optically monitored by the VITEK 2 Systems for growth within each well in the card throughout the incubation cycle. At the completion of incubation, results are automatically calculated once a predetermined growth threshold is reached. A report is then generated that contains the MIC value and the interpretive category result (S, I, R) for each antibiotic contained on the card. The MIC ranges, interpretive criteria and equivalent concentrations for testing Enterobacteriaceae are as follows: | VITEK 2 AST-GN | Equivalent Standard Method Concentration by Efficacy in μg/mL | MIC Ranges and FDA/CLSI Categories MIC* in μg/mL: | | | | --- | --- | --- | --- | --- | | | | S | I | R | | Trimethoprim/Sulfamethoxazole | 1/19, 4/76, and 16/304 μg/mL | ≤2/38 | | ≥4/76 | ** S = Susceptible; I = Intermediate; R = Resistant J. Substantial Equivalence Information: 1. Predicate device name(s): VITEK 2 Gram Negative Meropenem 2. Predicate K number(s): k091899 {3} 3. Comparison with predicate: | Similarities | | | | --- | --- | --- | | Item | Device | Predicate | | Intended Use | Determining quantitative and qualitative susceptibility to antimicrobial agents | Same | | Inoculation and test organism | Isolated colonies of Gram Negative bacilli | Same | | Instrument | Test are run on both the VITEK 2 and VITEK 2 Compact Systems | Same | | Test Card | The VITEK 2 card, including base broth | Same | | Differences | | | | --- | --- | --- | | Item | Device | Predicate | | Antibiotic | Trimethoprim/Sulfamethoxazole-specific concentrations | Meropenem-specific concentrations | | Reading algorithm | Growth Pattern Analysis-Unique to Trimethoprim/Sulfamethoxazole | Discriminate Analysis Unique to Meropenem | K. Standard/Guidance Document Referenced (if applicable): “Class II Special Controls Guidance Document: Antimicrobial Susceptibility Test (AST) Systems; Guidance for Industry and FDA” http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm071462.pdf Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically, Approved Standard -7th Edition, Document M7-A8 Performance Standards for Antimicrobial Susceptibility Testing – 18th Informational Supplement, M100-S19 L. Test Principle: Automated growth based detection using attenuation of light measured by an optical scanner. The optics used in the systems use visible light to directly measure organism growth. Transmittance optics are based on an initial light reading of a well before significant growth has begun. Periodic light transmittance samplings of the same well measure organism growth by how much light is prevented from going through the well. The VITEK 2 System monitors the growth of each well in the card over a defined period of time. An interpretive call is made between 4 and 16 hours for a {4} "rapid" read but may be extended to 18 hours in some instances. At the completion of the incubation cycle, a report is generated that contains the MIC value along with the interpretive category result for each antibiotic on the card. The VITEK 2 AST Gram Negative card has the following Trimethoprim/Sulfamethoxazole concentrations of 1/19, 4/76, and 16/304 µg/mL. The MIC result range for the VITEK 2 card is ≤20 (1/19) to ≥320 (16/304) µg/mL. ## M. Performance Characteristics (if/when applicable): ### 1. Analytical performance: #### a. Precision/Reproducibility: Reproducibility was conducted at three study sites. Ten Gram Negative isolates were tested at each site and testing was performed in triplicate over three days with VITEK 2 AST GN-SXT. The testing was performed using both the manual dilution method and the automated dilution mode. Testing was conducted on the VITEK 2 instrument. For the sake of reproducibility calculations, off-scale values are handled in two ways; "best case" and "worst case" scenarios. Best case calculation for reproducibility assumes the off-scale result is within one well from the mode MIC value. Worst case calculation for reproducibility assuming the off-scale result is greater than one well from the mode MIC value. The overall reproducibility was >95% with +/- one dilution observation. For Automatic Dilution, the VITEK 2 AST GN-SXT gave overall reproducibility values of 97.8% and 87.8% based on best case and worst case calculations, respectively. For Manual Dilution, the VITEK 2 AST GN-SXT gave overall reproducibility values of 98.2% and 88.5% based on best case and worst case calculations, respectively. A similar reproducibility study was conducted by testing on the VITEK 2 Compact instrument. The VITEK 2 AST GN-SXT card gave a reproducibility of 100% by Manual Dilution. Only Manual Dilution testing was conducted since the VITEK 2 Compact system does not have a functionality to support automatic dilution to inoculate the card. #### b. Linearity/assay reportable range: Not applicable #### c. Traceability, Stability, Expected values (controls, calibrators, or methods): The recommended QC isolates were tested on every test occasion with the reference method and the VITEK 2 System. The reference method QC results were in range for every day tested. The VITEK 2 and reference testing was 5 {5} performed a minimum of twenty times by each method at each site. There were some instances where either VITEK or reference results were out of range. In such instances where any organism was out of range for the reference method, all data from that day's testing was considered invalid and that day's testing was repeated. Quality Control was performed during the studies using both the auto-dilution and the manual method of diluting the organisms on the VITEK 2 System. Results demonstrated that methods were comparable. Quality Control Results with the VITEK 2 System | Organism | Concentration (μg/mL) | Auto Dilution | | Manual Dilution | | | --- | --- | --- | --- | --- | --- | | | | Reference | VITEK 2 | Reference | VITEK 2 | | Escherichia coli ATCC 25922 | ≤10 (0.5/9.5) | 101 | | 85 | | | | ≤20 (1/19)* | | 101 | | 85 | | Acceptable MIC range: ≤10 (0.5/9.5) μg/mL | 40 (2/38* | | | | | | | 80 (4/76)* | | | | | | | 160 (8/152)* | | | | | | | 320 (16/304)* | | | | | | | 640 (32/608) | | | | | | | >640 (32/608) | | | | | | | | | | | | | Pseudomonas aeruginosa ATCC 27853 | ≤10 (0.5/9.5) | | | | | | | ≤20 (1/19)* | | 4 | | 5 | | | 40 (2/38* | | | | | | Acceptable MIC range: 160 (8/152)-640 (32/608) μg/mL | 80 (4/76)* | | 1 | | | | | 160 (8/152)* | 20 | 5 | 20 | 3 | | | 320 (16/304)* | 41 | 87 | 37 | 78 | | | 640 (32/608) | 33 | | 26 | | | | >640 (32/608) | 3 | | 3 | | * VITEK Card Result Range is ≤20 (1/19) to ≥320 (16/304) μg/mL. VITEK reports MIC values as a combined concentration of Trimethoprim plus Sulfamethoxazole based on a ratio of 1:19. Quality Control results for the VITEK 2 System using either inoculation dilution method demonstrated that the VITEK 2 System could produce the expected QC ranges with an acceptable rate. A similar QC study was conducted to evaluate the VITEK 2 Compact System. Results were compared to the expected CLSI QC results. All results for the Vitek 2 Compact System were within the expected QC ranges 100% of the time. {6} Quality Control Results with the VITEK 2 Compact System | Organism | Concentration (μg/mL) | Reference | VITEK 2 GP SXT | | --- | --- | --- | --- | | | | | Manual Dilution | | Escherichia coliATCC 25922 | ≤10 (0.5/9.5) | 60 | | | Acceptable MIC range: ≤10 (0.5/9.5) μg/mL | ≤20 (1/19)* | | 60 | | | 40 (2/38* | | | | | 80 (4/76)* | | | | | 160 (8/152)* | | | | | 320 (16/304)* | | | | | 640 (32/608) | | | | | >640 (32/608) | | | | | | | | | Pseudomonas aeruginosa ATCC 27853 | ≤10 (0.5/9.5) | | | | | ≤20 (1/19)* | | | | | 40 (2/38* | | | | Acceptable MIC range: 160 (8/152)-640 (32/608) μg/mL | 80 (4/76)* | | | | | 160 (8/152)* | | 7 | | | 320 (16/304)* | 60 | 31 | | | 640 (32/608) | | 22 | | | >1280 (64/1216) | | | * VITEK Card Result Range is ≤20 (1/19) to ≥320 (16/304) μg/mL. VITEK reports MIC values as a combined concentration of Trimethoprim plus Sulfamethoxazole based on a ratio of 1:19. Inoculum density control was monitored using the DensiChek2 instrument. This was standardized weekly with all results recorded and in the expected range. d. Detection limit: Not applicable. e. Analytical specificity: Not applicable. f. Assay cut-off: Not applicable {7} 8 2. Comparison studies: a. Method comparison with predicate device: Performance was established through a clinical study which was conducted at three external sites. A total of 280 clinical isolates were tested by VITEK 2 AST GN-SXT with the VITEK® 2 System. The vast majority of the isolates were recently isolated from clinical specimens. A challenge set consisting of 87 isolates was also evaluated. Testing was done using the VITEK 2 AST GN-SXT and the broth microdilution method using cation-adjusted Mueller Hinton (MH) broth. The MH broth was incubated at 35°C in ambient air for up to 16-20 hours. The inoculum was prepared with direct colony suspension. The testing included both fresh clinical isolates and stock isolates along with a challenge set with known results. Two methods of inoculation (manual and auto dilution) were evaluated. Clinical testing was performed using the automated method of inoculation and the challenge set was tested using both the manual and the auto dilution method. A comparison was provided to the reference method with the following agreement. AutoDilution | Organism Group | CA Tot | CA N | CA % | #R | # vmj | # maj | # min | | --- | --- | --- | --- | --- | --- | --- | --- | | Enterobacteriaceae | | | | | | | | | CLINICAL | 280 | 280 | 100 | 47 | 0 | 0 | 0 | | CHALLENGE | 87 | 87 | 100 | 8 | 0 | 0 | 0 | | COMBINED (CLINICAL AND CHALLENGE) | 367 | 367 | 100 | 55 | 0 | 0 | 0 | maj-major discrepancies; vmj-very major discrepancies; min-minor discrepancies Essential agreement (EA) is when the VITEK 2 panels agree with the reference test panel results exactly or within one doubling dilution of the reference method. Category agreement (CA) is when the VITEK 2 panel result interpretation agrees exactly with the reference panel result interpretation. Evaluable EA is when the MIC result is on scale for both the VITEK 2 and the reference and have on-scale EA. No evaluation could be made on the basis of EA because of the small number of evaluable results. However, CA was 100% for both clinical and challenge isolates. Also, another study on the VITEK 2 Compact Systems demonstrated acceptable CA (See below). A total of 87 Challenge Enterobacteriaceae isolates were also tested in the VITEK 2 Compact using the manual dilution method. A comparison was provided to the reference method with the following agreement. {8} 9 Manual Dilution | Organism Group | CA Tot | CA N | CA % | #R | # vmj | # maj | # min | | --- | --- | --- | --- | --- | --- | --- | --- | | Enterobacteriaceae CHALLENGE | 87 | 85 | 97.7 | 8 | 0 | 2 | 0 | 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 4. Clinical cut-off: Not Applicable 5. Expected values/Reference range: FDA Interpretive criteria MIC in $\mu \mathrm{g} / \mathrm{ml}$ for Enterobacteriaceae are: $$ S = \leq 2 / 38 \ \mu \mathrm{g} / \mathrm{mL} $$ $$ R = \geq 4 / 76 \ \mu \mathrm{g} / \mathrm{mL} $$ N. Proposed Labeling: The labeling is sufficient and it satisfies the requirements of 21 CFR section 809.10. O. Conclusion: The submitted information in this premarket notification is complete and supports a substantial equivalence decision.