Etest Ceftaroline (0.002 - 32ug/ml)

{0} Page 1 of 11 # 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY ASSAY ONLY TEMPLATE A. 510(k) Number: k151873 B. Purpose for Submission: To obtain clearance for the addition of ceftaroline at concentrations 0.002 – 32 µg/mL to the Etest strip for susceptibility testing of fastidious species (S. pneumoniae, S. agalactiae, Haemophilus influenzae). C. Measurand: Ceftaroline 0.002 – 32 µg/mL D. Type of Test: Quantitative AST growth based detection E. Applicant: bioMérieux, Inc F. Proprietary and Established Names: Etest® Ceftaroline (0.002 – 32 µg/mL) G. Regulatory Information: 1. Regulation section: 866.1640 Antimicrobial Susceptibility Test Powder 2. Classification: II 3. Product code: JWY - Manual Antimicrobial Test Systems {1} 4. Panel: 83 - Microbiology H. Intended Use: 1. Intended use(s): Etest® is a quantitative technique for determining the antimicrobial susceptibility testing of Gram-negative and Gram positive aerobic bacteria such as Enterobacteriaceae, Pseudomonas, Staphylococcus and Enterococcus species and fastidious bacteria, such as anaerobes, N. gonorrhoeae, S. pneumoniae, Streptococcus and Haemophilus species. The system comprises a predefined antibiotic gradient which is used to determine the Minimum Inhibitory Concentration (MIC), in µg/mL, of different antimicrobial agents against microorganisms as tested on agar media using overnight incubation. 2. Indication(s) for use: Etest® is a quantitative technique for determining the antimicrobial susceptibility testing of both non-fastidious Gram-negative and Gram positive aerobic bacteria such as Enterobacteriaceae, Pseudomonas, Staphylococcus and Enterococcus species and fastidious bacteria, such as anaerobes, N. gonorrhoeae, S. pneumoniae, Streptococcus and Haemophilus species. The system comprises a predefined antibiotic gradient which is used to determine the Minimum Inhibitory Concentration (MIC), in µg/mL, of different antimicrobial agents against microorganisms as tested on agar media using overnight incubation. This submission is for the additional indications for the antimicrobial Etest Ceftaroline at concentrations of 0.002 – 32 µg/mL. Etest® Ceftaroline has been shown to be active in vitro against fastidious strains of the microorganisms listed below, according to the FDA label for this antimicrobial agent: Streptococcus pneumoniae Streptococcus agalactiae Haemophilus influenzae 3. Special conditions for use statement(s): For prescription use Isolates yielding MIC results other than “Susceptible” should be submitted to a reference laboratory for further testing. Page 2 of 11 {2} 4. Special instrument requirements: Manual readings only I. Device Description: Etest® consists of a thin, inert and non-porous plastic strip, 5mm wide and 60 mm long. One side of the strip carries a two-letter code designating the identity of the antibiotic and is calibrated with MIC values in terms of µg/mL. A predefined exponential gradient of the dried and stabilized antibiotic covers a continuous concentration range across 15 two-fold dilutions of a conventional MIC method. The current FDA pharmaceutical drug label includes the following indicated fastidious organisms: [S. agalactiae (skin isolates only), S. pneumoniae and H. influenzae (Community Acquired Bacterial Pneumonia isolates only)] $S = \leq 0.5 \mu \mathrm{g} / \mathrm{mL}^*$ *The current absence of resistant isolates precludes defining any results other than "Susceptible." Isolates yielding MIC results other than "Susceptible" should be submitted to a reference laboratory for further testing. J. Substantial Equivalence Information: 1. Predicate device name(s): Etest® Ceftaroline 2. Predicate 510(k) number(s): k121002 3. Comparison with predicate: | Similarities | | | | --- | --- | --- | | Item | Device | Predicate | | Intended Use | Quantitative susceptibility to antimicrobial agents | Same | | | | | | Antibiotic | Ceftaroline 0.002-32 μg/mL | Same | | Incubation | 35°; 5% CO2; 20-24 hours | Same | | Inoculation | Isolated colonies from culture used | Same | | Result | MIC | Same | | Concentration Range | 0.002 – 32 μg/mL | Same | {3} | Differences | | | | --- | --- | --- | | Item | Device | Predicate | | Organisms | Community-Acquired Bacterial Pneumonia (CABP): Streptococcus pneumoniae Haemophilus influenzae Skin infections: Streptococcus agalactiae | Skin infections: Staphylococcus aureus (including methicillin-susceptible and resistant isolates) | | Reading time | Etest compared to Broth Microdilution reference method read at 18 and at 23 hours | Etest results compared to Broth Microdilution reference method read at 16-20 hours. | ## K. Standard/Guidance Document Referenced (if applicable): “Class II Special Controls Guidance Document: Antimicrobial Susceptibility Test (AST) Systems; Guidance for Industry and FDA”; CLSI M7-A9 “Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard, January 2009” CLSI M100-S24 “Performance Standards for Antimicrobial Susceptibility Testing: Twentieth Informational Supplement, January 2011” ## L. Test Principle: The Etest® gradient technology is based on a combination of the concepts of dilution and diffusion test methods for susceptibility testing. Etest® directly quantifies antimicrobial susceptibility in terms of discrete MIC values. When the Etest® strip is applied to an inoculated agar plate, the antibiotic is immediately released from the plastic surface into the agar. A predefined, continuous gradient of antibiotic concentrations is created and maintained directly underneath the strip. After incubation whereby bacterial growth becomes visible, a symmetrical inhibition ellipse centered along the strip will be seen. The MIC value in $\mu \mathrm{g} / \mathrm{mL}$ is read where the ellipse edge intersects the strip. Since Etest® generates MIC values which fall between two-fold dilutions for interpretation; the MIC value read must be recorded to the next two-fold dilution. ## M. Performance Characteristics (if/when applicable): 1. Analytical performance: a. Precision/Reproducibility: {4} Twenty-five isolates of each organism (Haemophilus influenzae, Streptococcus agalactiae and Streptococcus pneumoniae) were tested at three external sites to determine site to site reproducibility. Results were within +/- one doubling dilution agreement as compared to the mode MIC value of Ceftaroline for all organisms at all sites and there were no off-scale results. The results were acceptable and demonstrated $\geq 95\%$ reproducibility. b. Linearity/assay reportable range: Not applicable c. Traceability, Stability, Expected values (controls, calibrators, or methods): The recommended QC isolates were tested a sufficient number of times with acceptable results with the reference method. The Etest® results demonstrate that the system can produce QC results in the recommended range (Tables 1 and 2). Table 1. Quality Control Data Read at 18 hours | ORGANISM | conc. | Reference Frequency | Etest® Frequency | | --- | --- | --- | --- | | Haemophilus influenzae ATCC 49247 Expected Results 0.032-0.125 | <0.032 | 1 | | | | 0.032 | 7 | 4 | | | 0.0.064 | 74 | 38 | | | 0.125 | 5 | 50 | | | >0.125 | | 1 | | Streptococcus pneumonia ATCC 49619 Expected Results 0.008-0.032 | <0.008 | | | | | 0.008 | 23 | 1 | | | 0.016 | 75 | 35 | | | 0.032 | 5 | 88 | | | >0.032 | | 2 | Table 2. Quality Control Data Read at 23 hours | ORGANISM | conc. | Reference Frequency | Etest® Frequency | | --- | --- | --- | --- | | Haemophilus influenzae ATCC 49247 Expected Results 0.032-0.125 | <0.032 | | | | | 0.032 | 7 | 4 | | | 0.0.064 | 74 | 48 | | | 0.125 | 6 | 50 | | | >0.125 | | 1 | | Streptococcus pneumonia ATCC 49619 Expected Results 0.008-0.032 | <0.008 | | | | | 0.008 | 6 | 1 | | | 0.016 | 92 | 35 | | | 0.032 | 5 | 88 | | | >0.032 | | 3 | {5} The quality control results are acceptable. The inoculum was prepared to match a 0.5 McFarland. Colony counts were performed periodically at each site to demonstrate that the inoculum procedure results were in the expected CFU/mL. d. Detection limit: Not Applicable e. Analytical specificity: Not Applicable f. Assay cut-off: Not Applicable 2. Comparison studies: Clinical testing was performed at three external and one internal sites. There were 694 clinical isolates, of which 225 were stock (31.7%), and a challenge set of 50 isolates of each organism claimed (H. influenzae, S. agalactiae and S. pneumoniae). A total of 150 challenge isolates was evaluated. a. Method comparison with predicate device: The CLSI recommended broth dilution reference panel was prepared and interpreted according to CLSI recommendations with the following modification: broth microdilution panels were read at 18 hours as indicated in the FDA approved pharmaceutical drug label for Ceftaroline. The 18 hour incubation is required due to degradation of Ceftaroline activity when incubation extends to 24 hours. Panels were re-incubated and read at 23 hours per the CLSI recommendation of 20-24 hour incubation. Etest was performed following Table 1 (Recommended Media and Inoculum) of the Generic Package Insert: Streptococcus pneumoniae and Streptococcus agalactiae were inoculated onto Mueller Hinton agar + 5% blood; Haemophilus influenzae isolates were inoculated onto HTM agar media. Isolated colonies from an overnight agar plate were emulsified in Mueller Hinton or HTM broth to achieve the specified inoculum turbidity compared to a 0.5 McFarland turbidity standard. In this submission, the suspension prepared in broth was used within 15 minutes of preparation. Testing conditions consisted of incubation at 35°C; 5% CO₂ for 20-24 hours. All Page 6 of 11 {6} isolates grew in the clinical and challenge studies. The clinical testing included both fresh clinical isolates and stock isolates along with a challenge set with known results. The following footnote was added to the package insert: "Refer to the FDA approved pharmaceutical antimicrobial agent package insert for interpreting and reporting results of Ceftaroline which has been shown to be active against the following organisms/corresponding clinical infections: Streptococcus agalactiae (skin infections isolates only), S. pneumoniae and H. influenzae (community acquired bacterial pneumonia isolates only)". A comparison was provided to the reference method with the following agreement (Tables 3 through 6). Table 3. Summary for Fastidious Species (Etest Compared to Reference Method Read at 18 Hours) | | EA Tot | EA # | EA% | Eval EA tot | Eval EA# | Eval EA % | CA# | CA% | NS | vmj | maj | min | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Clinical | 694 | 645 | 92.9 | 677 | 639 | 94.4 | 694 | 100 | 0 | 0 | 0 | NA | | Challenge | 150 | 148 | 98.7 | 146 | 145 | 99.3 | 150 | 100 | 0 | 0 | 0 | NA | | Combined | 844 | 793 | 94.0 | 823 | 784 | 95.3 | 844 | 100 | 0 | 0 | 0 | NA | Table 4. Summary for Fastidious Species (Etest Compared to Reference Method Read at 23 Hours) | | EA Tot | EA # | EA% | Eval EA tot | Eval EA# | Eval EA % | CA# | CA % | NS | vmj | maj | min | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Clinical | 694 | 662 | 95.4 | 687 | 658 | 95.8 | 694 | 100 | 0 | 0 | 0 | NA | | Challenge | 150 | 149 | 99.3 | 147 | 146 | 99.3 | 150 | 100 | 0 | 0 | 0 | NA | | Combined | 844 | 811 | 96.1 | 834 | 804 | 96.4 | 844 | 100 | 0 | 0 | 0 | NA | Table 5. Performance of Clinical and Challenge Isolates by Species (Reference Method Read at 18 hours) | | TOT | EA N | EA % | Eval Tot | Eval EA N | Eval EA % | CA N | CA % | No. NS | min | maj | vmj | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Streptococcus pneumoniae | | | | | | | | | | | | | | Clinical | 233 | 219 | 94.0 | 231 | 218 | 94.4 | 233 | 100 | 0 | NA | 0 | 0 | | Challenge | 50 | 50 | 100 | 50 | 50 | 100 | 50 | 100 | 0 | NA | 0 | 0 | | Combined | 283 | 269 | 95.1 | 281 | 268 | 95.4 | 283 | 100 | 0 | NA | 0 | 0 | | Streptococcus agalactiae | | | | | | | | | | | | | | Clinical | 226 | 209 | 92.5 | 219 | 208 | 95.0 | 226 | 100 | 0 | NA | 0 | 0 | | Challenge | 50 | 50 | 100 | 50 | 50 | 100 | 50 | 100 | 0 | NA | 0 | 0 | | Combined | 276 | 259 | 93.8 | 269 | 258 | 95.9 | 276 | 100 | 0 | NA | 0 | 0 | | Haemophilus influenzae | | | | | | | | | | | | | | Clinical | 235 | 217 | 92.3 | 227 | 213 | 93.8 | 235 | 100 | 0 | NA | 0 | 0 | {7} Table 6. Performance of Clinical and Challenge Isolates by Species (Reference Method Read at 23 hours) | | TOT | EA N | EA % | Eval Tot | Eval EA N | Eval EA % | CA N | CA % | No. NS | min | maj | vmj | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Streptococcus pneumoniae | | | | | | | | | | | | | | Clinical | 233 | 222 | 95.3 | 231 | 221 | 95.7 | 233 | 100 | 0 | NA | 0 | 0 | | Challenge | 50 | 50 | 100 | 50 | 50 | 100 | 50 | 100 | 0 | NA | 0 | 0 | | Combined | 283 | 272 | 96.1 | 281 | 271 | 96.4 | 283 | 100 | 0 | NA | 0 | 0 | | Streptococcus agalactiae | | | | | | | | | | | | | | Clinical | 226 | 219 | 96.9 | 225 | 219 | 97.3 | 226 | 100 | 0 | NA | 0 | 0 | | Challenge | 50 | 50 | 100 | 50 | 50 | 100 | 50 | 100 | 0 | NA | 0 | 0 | | Combined | 276 | 269 | 97.5 | 275 | 269 | 97.8 | 276 | 100 | 0 | NA | 0 | 0 | | Haemophilus influenzae | | | | | | | | | | | | | | Clinical | 235 | 221 | 94.0 | 231 | 218 | 94.4 | 235 | 100 | 0 | NA | 0 | 0 | | Challenge | 50 | 49 | 98.0 | 47 | 46 | 97.9 | 50 | 100 | 0 | NA | 0 | 0 | | Combined | 285 | 270 | 94.7 | 278 | 264 | 95.0 | 285 | 100 | 0 | NA | 0 | 0 | EA-Essential Agreement CA-Category Agreement NS-not susceptible isolates min-minor discrepancies maj- major discrepancies vmj-very major discrepancies Essential agreement (EA) is when the Etest® results agree with the reference test panel results exactly or within one doubling dilution of the reference method. Category agreement (CA) is when the Etest® result interpretation agrees exactly with the reference panel result interpretation. The overall combined $\% \mathrm{EA}$ and $\% \mathrm{CA}$ consistently meet the acceptance criteria of greater than or equal to $90\%$ . ## MIC Trends: Using the data provided by the sponsor in the diagonal table format recommended in the AST Guidance, an analysis was conducted to check for trending in MIC values. A higher reading trend was observed in the overall performance of S. agalactiae, S. pneumoniae and H. influenzae compared to the CLSI broth micro-dilution method when read at 18 hours and 23 hours, as summarized in Tables 7 and 8 below respectively. {8} Table 7. Trending of Results in Combined Clinical and Challenge Study (Reference Method Read at 18 Hours) | Organism | Difference in MIC as Compared to the CLSI Reference Method | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | ≤ -3 | -2 | -1 | 0 | +1 | +2 | ≥ +3 | Total | | S. agalactiae | 0 | 0 | 2.9% (8/276) | 53.6% (148/276) | 37.3% (103/276) | 6.1% (15/276) | 0.7% (2/276) | 276 | | S. pneumoniae | 0 | 0 | 2.4% (7/283) | 50.1% (142/283) | 42.4% (120/283) | 4.9% (13/283) | 0.3% (1/283) | 283 | | H. influenzae | 0.35% (1/285) | 0.7% (2/285) | 8.07% (23/285) | 48.07% (137/285) | 36.8% (105/285) | 4.5% (13/285) | 1.4% (4/285) | 285 | | Total | 0.11% (1/844) | 0.2% (2/844) | 4.5% (38/844) | 50.6% (427/844) | 38.6% (328/844) | 5.2% (41/844) | 0.4% (7/844) | 844 | Table 8. Trending of Results in Combined Clinical and Challenge Study (Reference Method Read at 23 Hours) | Organism | Difference in MIC as Compared to the CLSI Reference Method | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | ≤ -3 | -2 | -1 | 0 | +1 | +2 | ≥+3 | Total | | S. agalactiae | 0 | 0 | 4.3% (12/276) | 57.2% 158/276 | 35.8% (99/276) | 2.5% (7/276) | 0 | 276 | | S. pneumoniae | 0 | 0 | 2.4% (7/283) | 53.7% (152/283) | 40% (113/283) | 3.8% (11/283) | 0 | 283 | | H. influenza | 0.3% (1/285) | 1.4% (4/285) | 8.7% (25/285) | 52% (148/285) | 34.03% (97/285) | 3.1% (9/285) | 0.3% (1/285) | 285 | | Total | 0.1% (1/844) | 0.4% (4/844) | 5.2% (44/844) | 54.2% (458/844) | 36.6% (309/844) | 3.1% (27/844) | 0.1% (1/844) | 844 | This trending and the potential for occurrence of major error(s) for Ceftaroline when testing S. agalactiae, S. pneumoniae and H. influenzae with E-test was addressed in the labeling by adding the following footnote under the interpretation table in labeling: "MIC values for fastidious Gram positive organisms tended to be one or more doubling dilution higher compared to the CLSI broth microdilution method. {9} The MIC results read at 18 hour were higher by one or more doubling dilution as follows: 43.4% (120/276) for S. agalactiae, 47.3% (134/283) for S. pneumoniae, and 42.8% (122/285) for H. influenzae. The MIC results read at 23 hours were higher by one or more doubling dilution as follows: 38.4% (106/276) for S. agalactiae, 43.8% (124/283) for S. pneumoniae, and 37.5% (107/285) for H. influenzae". 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: | Organism and Infection Source | Interpretive Criteria | | --- | --- | | Streptococcus agalactiae (skin isolates only) | S= ≤ 0.5 μg/mL** | | Streptococcus pneumoniae (CABP* isolates only) | | | Haemophilus influenzae (CABP isolates only) | | *Community Acquired Bacterial Pneumonia **The current absence of resistant isolates precludes defining any results other than "Susceptible." Isolates yielding MIC results other than "Susceptible" should be submitted to a reference laboratory for further testing. The Interpretative criteria, QC isolates and the expected ranges are the same as recommended by the CLSI and the FDA. All values will be included in the package insert. N. Proposed Labeling: The labeling is sufficient and it satisfies the requirements of 21 CFR Part 809.10. Page 10 of 11 {10} O. Conclusion: The submitted information in this premarket notification is complete and supports a substantial equivalence decision. Page 11 of 11