Sensititre 18-24 hour MIC or Breakpoint Susceptibility System with Cefiderocol in the dilution range of 0.03-64 µg/ml

{0} FDA U.S. FOOD & DRUG ADMINISTRATION # 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY ASSAY ONLY ## I Background Information: A 510(k) Number K193538 B Applicant Thermo Fisher Scientific C Proprietary and Established Names Sensititre 18-24 hour MIC or Breakpoint Susceptibility System with Cefiderocol in the dilution range of 0.03-64 µg/mL D Regulatory Information | Product Code(s) | Classification | Regulation Section | Panel | | --- | --- | --- | --- | | JWY, LRG, LTT | 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 addition of Cefiderocol at concentrations of 0.03 – 64 µg/mL to the Sensititre 18-24-hour MIC or Breakpoint Susceptibility System for testing Gram negative isolates B Measurand: Cefiderocol in the dilution range of 0.03 - 64 µg/mL C Type of Test: Quantitative Antimicrobial Susceptibility Test (AST), growth-based detection Food and Drug Administration 10903 New Hampshire Avenue Silver Spring, MD 20993-0002 www.fda.gov {1} K193538 - Page 2 of 12 # III Intended Use/Indications for Use: ## A Intended Use(s): The Sensititre MIC and Breakpoint Susceptibility system is an *in vitro* diagnostic product for clinical susceptibility testing of non-fastidious gram negative isolates comprising of *Enterobacteriaceae*, *Pseudomonas aeruginosa* and other non-*Enterobacteriaceae* and of non-fastidious gram positive isolates, comprising of *Staphylococcus* spp., *Enterococcus* spp., and Beta-hemolytic *Streptococci* other than *S. pneumoniae*. ## B Indication(s) for Use: The Sensititre 18-24 hour MIC or Breakpoint Susceptibility System is an *in vitro* diagnostic product for clinical susceptibility testing of non fastidious isolates. This 510(k) is for Cefiderocol in the dilution range of 0.03-64 µg/mL for testing non-fastidious Gram negative organisms on the Sensititre 18-24 hour MIC panel. Cefiderocol has been shown to be active both clinically and *in vitro* against the following organisms according to the FDA drug label: - Gram-negative bacteria - *Escherichia coli* - *Enterobacter cloacae* complex - *Klebsiella pneumoniae* - *Proteus mirabilis* - *Pseudomonas aeruginosa* ## C Special Conditions for Use Statement(s): Rx - For Prescription Use Only Studies of Cefiderocol with *Enterobacteriaceae* and *Pseudomonas aeruginosa* were performed using the AIM autoinoculator inoculation method and OptiRead and VIZION reading methods only. The use of alternative inoculation methods or alternative reading methods when testing Cefiderocol have not been evaluated. The ability of the Sensititre system to detect resistance to Cefiderocol in the following species is unknown because resistant strains were not available at the time of comparative testing: *P. mirabilis* and *P. aeruginosa*. Isolates yielding cefiderocol MIC results suggestive of a resistant interpretative category should be submitted to a reference laboratory for further testing. ## D Special Instrument Requirements: - Sensititre AIM for device inoculation - Sensititre VIZION or OptiRead for plate reading # IV Device/System Characteristics: {2} # A Device Description: Sensititre MIC Susceptibility MIC panels are multi-well microtiter plates, dosed with dried, stabilized antimicrobials. It is a miniaturized version of the classic broth dilution method and can provide both qualitative and quantitative susceptibility results. After inoculation, plates are sealed with an adhesive seal, incubated at 34 - 36 °C for 18 - 24 hours and examined for bacterial growth. Antimicrobial susceptibility test results can be determined by reading growth using the digital device (VIZION) or automatically on an autoreader (OptiRead) using fluorescence. # B Principle of Operation: The Sensititre 18-24 hour MIC or Breakpoint Susceptibility System includes multi-well plastic microtiter plates that contain doubled dilution of antibacterial agents. Each plate includes antimicrobial agents at appropriate dilutions. Results can be read by the digital device, VIZION, or by use of an automated reader (OptiRead). The VIZION allows the panel image to be displayed on a touch screen directly from a video camera and allows the user to visually determine MIC results. The Sensititre OptiRead utilizes fluorescence technology to read the microbroth dilution plates after 18 to 24 hours incubation. The technology involves the detection of bacterial growth by monitoring the activity of specific surface enzymes produced by the test organism. Growth is determined by generating a fluorescent product from a fluorogenic substrate. The substrate is prepared by conjugating a fluorescent compound to the specific enzyme substrates with a bond which prevents fluorescence. The enzymatic action of the bacterial surface enzymes on the substrate cleaves the bond releasing fluorescence. The amount of fluorescence detected is directly related to bacterial growth. The MIC is determined by observing the lowest dilution of antimicrobial agent that inhibits growth of the organism. The substrate can be added to the inoculum broth which is dispensed into the test plate at the same time as the test organism, or, the plates can be prepared with the substrate already added to each micro-well. # V Substantial Equivalence Information: # A Predicate Device Name(s): Sensititre 18-24 hour MIC or Breakpoint Susceptibility System with Omadacycline in the dilution range of $0.03 - 32\mu \mathrm{g / ml}$ # B Predicate 510(k) Number(s): K183033 # C Comparison with Predicate(s): Table 1. Comparison with the Predicate Device | Device & Predicate Device(s): | Device K193538 | Predicate K183033 | | --- | --- | --- | | Device Trade Name | Sensititre 18-24 hour MIC or Breakpoint Susceptibility System with Cefiderocol in the dilution range of 0.03-64 μg/ml | Sensititre 18-24 hour MIC or Breakpoint Susceptibility System with Omadacycline in the dilution range of | K193538 - Page 3 of 12 {3} K193538 - Page 4 of 12 | | | 0.03-32 µg/ml | | --- | --- | --- | | **General Device Characteristic Similarities** | | | | Intended Use/Indications For Use | The Sensititre MIC and Breakpoint Susceptibility system is an *in vitro* diagnostic product for clinical susceptibility testing of non-fastidious Gram negative isolates, comprising of *Enterobacteriaceae*, *Pseudomonas aeruginosa*, and other non-*Enterobacteriaceae* and of non-fastidious gram positive isolates, comprising of *Staphylococcus* sp., *Enterococcus* sp., and Beta hemolytic *Streptococci* other than *S. pneumoniae*. | Same | | Test Panel | 96 well plate is dosed with selected antimicrobial agents and substrate for the fluorescent reads, then dried. The bacterial suspension in the appropriate broth is used to rehydrate the plate | Same | | Test Organism | Non-fastidious Gram negative isolates | Same | | Read Method | Results can be read using the following methods: 1) Automatically with the OptiRead (fluorescent substrate technology) 2) On the VIZION (digital viewing device) | Same | | Incubation | 18-24 hours | Same | | **General Device Characteristic Differences** | | | | Antimicrobial Agent | Cefiderocol | Omadacycline | | Antimicrobial Concentrations | 0.03 – 64 µg/mL | 0.03 – 32 µg/mL | {4} 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. Performance Standards for Antimicrobial Susceptibility Testing. 29th ed. CLSI supplement M100. Wayne, PA: Clinical and Laboratory Standards Institute; 2019. CLSI. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically. 11th ed. CLSI standard M07. Wayne, PA: Clinical and Laboratory Standards Institute; 2018. VII Performance Characteristics (if/when applicable): A Analytical Performance: 1. Precision/Reproducibility: A reproducibility study was performed at three sites using a panel comprised of 10 non-fastidious Gram negative organisms including one *P. aeruginosa* and nine strains of *Enterobacteriaceae*: (*K. pneumoniae* (three isolates), *E. cloacae* (two isolates), *E. coli* (four isolates). All isolates were tested in triplicate over three days with each read method (i.e., VIZION and OptiRead). The Sensititre Aim inoculator was used for plate inoculation. The mode MIC value was determined and the reproducibility was calculated based on MIC values falling within ±1 dilution of the mode MIC value. Reproducibility was 95% for best case scenario and 84.8% for worst case scenario for both read methods and was considered to be acceptable. The <95% worst case scenario performance was due to a single *E. cloacae* isolate for which all MIC values for Cefiderocol were off-scale. 2. Linearity: Not applicable 3. Analytical Specificity/Interference: Not applicable 4. Assay Reportable Range: Not applicable K193538 - Page 5 of 12 {5} # 5. Traceability, Stability, Expected Values (Controls, Calibrators, or Methods): Quality control strains recommended by the CLSI were tested with Cefiderocol at three sites. The QC organisms tested were E. coli ATCC 25922 and P. aeruginosa ATCC 27853. The QC strains were initially tested a minimum of 20 times per site and read using the VIZION and OptiRead (Table 2). Additional QC testing was performed during further clinical performance testing of clinical and challenge isolates (Table 3). The results demonstrate that the Sensititre 18-24 hour MIC or Breakpoint panel with Cefiderocol produced quality control results for E. coli ATCC 25922 in the recommended range $>95\%$ of the time (Table 2 and Table 3). Quality control results for P. aeruginosa ATCC 27853 were not in the recommended range $95\%$ of the time using the VIZION and OptiRead method during initial testing (Table 2). In order to address the lower performance for P. aeruginosa ATCC 27853, additional quality control study was conducted which showed results within the expected range $100\%$ of the time (Table 3) and was considered acceptable. Quality control results for P. aeruginosa ATCC 27853 were not in the recommended range $95\%$ of the time with the reference method during both phases of the method comparison study. However, these data were considered acceptable and had no impact on clinical or challenge isolate test results since no P. aeruginosa clinical or challenge isolates were tested during days quality control results were out of recommended range. When the strains were tested the following day (per protocol), all quality control results were in-range. Furthermore, 19 additional QC tests were performed on 11 frozen reference panels and were $100\%$ within the recommended range using the CLSI reference method (data not shown). Table 2. Quality Control Results for Sensititre 18 - 24 hour MIC or Breakpoint Susceptibility System with Cefiderocol with the VIZION and OptiRead Methods | QC Organism | Cefiderocol Range (μg/mL) | Concentration (μg/mL) | Reference | Sensititre | | | --- | --- | --- | --- | --- | --- | | | | | | Read method | | | | | | | VIZION | OptiRead | | E. coli ATCC 25922a | 0.06-0.5 | 0.03 | 0 | 0 | 0 | | | | 0.06 | 0 | 1 | 1 | | | | 0.12 | 11 | 20 | 20 | | | | 0.25 | 50 | 41 | 40 | | | | 0.5 | 1 | 2 | 2 | | | | 1 | 0 | 0 | 1 | | P. aeruginosa ATCC 27853b | 0.06-0.5 | 0.03 | 0 | 0 | 0 | | | | 0.06 | 0 | 0 | 0 | | | | 0.12 | 1 | 4 | 2 | | | | 0.25 | 22 | 30 | 27 | | | | 0.5 | 34 | 25 | 26 | | | | 1 | 5 | 5 | 9 | $^{\mathrm{a}}$ E. coli ATCC 25922 in-range QC results: Reference, $100\%$ ; VIZION, $100\%$ ; OptiRead, $98.4\%$ bP. aeruginosa ATCC 27853 in-range QC results: Reference, $91.9\%$ ; VIZION, $85.9\%$ ; OptiRead, $92.2\%$ K193538 - Page 6 of 12 {6} Table 3. Additional Quality Control Results for Sensititre 18 – 24 hour MIC or Breakpoint Susceptibility System with Cefiderocol with the VIZION and OptiRead Methods | QC Organism | Cefiderocol Range (μg/mL) | Concentration (μg/mL) | Reference | Sensititre | | | --- | --- | --- | --- | --- | --- | | | | | | Read method | | | | | | | VIZION | OptiRead | | E. coli ATCC 25922^{a} | 0.06-0.5 | 0.03 | 0 | 2 | 2 | | | | 0.06 | 0 | 17 | 18 | | | | 0.12 | 6 | 27 | 28 | | | | 0.25 | 56 | 22 | 20 | | | | 0.5 | 9 | 6 | 5 | | | | 1 | 0 | 0 | 0 | | P. aeruginosa ATCC 27853^{b} | 0.06-0.5 | 0.03 | 0 | 0 | 0 | | | | 0.06 | 0 | 3 | 3 | | | | 0.12 | 9 | 4 | 18 | | | | 0.25 | 38 | 42 | 42 | | | | 0.5 | 18 | 25 | 11 | | | | 1 | 6 | 0 | 0 | | | | 1 | 5 | 5 | 9 | $^{a}$E. coli ATCC 25922 in-range QC results: Reference, 100%; VIZION, 97.3%; OptiRead, 97.3% $^{b}$P. aeruginosa ATCC 27853 in-range QC results: Reference, 91.5%; VIZION, 100%; OptiRead, 100% Inoculum Density. Inoculum density checks were performed a sufficient number of times; all organism suspensions were in the acceptable range. Purity Checks. Purity checks were performed on all isolates following plate inoculation. Only results from pure cultures were evaluated. Growth failures. All gram-negative isolates tested showed growth in the Sensititre panels. 6. Detection Limit: Not applicable 7. Assay Cut-Off: Not applicable B Comparison Studies: 1. Method Comparison with Predicate Device: For this review, the interpretative criteria are applied to Enterobacteriaceae and Pseudomonas aeruginosa according to the FDA STIC website. As required under 511A(2)(2)(B) of the Federal Food, Drug and Cosmetic Act, the following statements are added to the Sensititre 18-24 hour MIC or Breakpoint Susceptibility System package insert: 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 K193538 - Page 7 of 12 {7} susceptibility information in those instances is unknown. The approved labeling for specific antimicrobial drugs provides the uses for which the antimicrobial drug is approved. Results obtained with Sensititre 18 – 24 hour MIC or Breakpoint Susceptibility System with Cefiderocol were compared to results obtained with the CLSI broth microdilution reference panel. To prepare the reference panel, drug dilutions were made using iron-depleted CAMHB as indicated in CLSI M100, 29th ed. Chelation was used for iron depletion, which also removed other cations (i.e., calcium, magnesium, and zinc). Following this process, cations were added back to the medium in the following concentrations: calcium 20-25 mg/L, magnesium 10-12.5 mg/L, and zinc 0.5-1.0 mg/L. The dried Sensititre panels have a similar media composition using an alternative preparation method to produce final media in accordance with CLSI requirements. Clinical testing was performed at three clinical study sites in the U.S. A total of 268 Enterobacteriaceae isolates were tested compromised of the following species: E. coli (90 isolates), E. cloacae (74 isolates), K. pneumoniae (89 isolates) and P. mirabilis (15 isolates). A total of 60 P. aeruginosa isolates were tested. All of the clinical isolates tested were fresh isolates. During the course of the clinical trial, all Sensititre dried MIC panels were inoculated using the Sensititre Autoinoculator (AIM) and the same panel was read on both the VIZION and the OptiRead in a blinded manner. The sponsor added the following limitations to the device labeling to reflect these inoculation and read methods: Studies of Cefiderocol with Enterobacteriaceae and Pseudomonas aeruginosa were performed using the AIM autoinoculator inoculation method and OptiRead and VIZION reading methods only. The use of alternative inoculation methods or alternative reading methods when testing Cefiderocol have not been evaluated. A total of 103 challenge isolates were tested at a single site. Species tested included E. coli (29 isolates), E. cloacae (16 isolates), K. pneumoniae (27 isolates), P. mirabilis (10 isolates), and P. aeruginosa (21 isolates). For the Enterobacteriaceae, results were evaluated for essential agreement (EA) and category agreement (CA). For CA evaluation, the breakpoints (≤2, 4, ≥8 μg/mL) were used as noted on the FDA-Recognized Susceptibility Test Interpretive Criteria Website (STIC) (https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm575163.htm). The results from clinical and challenge testing determined with the VIZION demonstrated a combined EA of 93.7% and CA of 92.0%. Of the 354 isolates tested by the VIZION, 264 (75%) were determined to have evaluable results with an EA of evaluable results of 91.7% (Table 4). Clinical and challenge isolate results for the Enterobacteriaceae determined with OptiRead demonstrated a combined EA of 92.9% and CA of 90.6%. Of the 354 isolates tested by the OptiRead, 262 (74%) were determined to have evaluable results with an EA of evaluable results of 90.5% (Table 5). There was one very major error for E. coli for both read methods, which was considered acceptable as a random error. For P. aeruginosa results were evaluated for essential agreement (EA) and category agreement (CA). For CA evaluation, the STIC-recognized breakpoints (≤1, 2, ≥4 μg/mL) were used. The results from clinical and challenge testing determined with the VIZION demonstrated a combined EA of 97.5% and CA of 94.8%. Of the 81 isolates tested by the VIZION, 79 (97.5%) were determined to have evaluable results with an EA of evaluable results of 97.5% (Table 6). Clinical and challenge isolate results for the P. aeruginosa determined with OptiRead demonstrated a combined EA of 97.5% and CA of 92.6%. Of the 81 isolates K193538 - Page 8 of 12 {8} tested by the OptiRead, 80 (99%) were determined to have evaluable results with an EA of evaluable results of 97.5% (Table 7). For *P. mirabilis* and *P. aeruginosa*, an insufficient number of resistant strains were encountered during the clinical evaluation. The sponsor included the following limitation in the device labeling: The ability of the Sensititre system to detect resistance to Cefiderocol in the following species is unknown because resistant strains were not available at the time of comparative testing: *P. mirabilis* and *P. aeruginosa*. Isolates yielding cefiderocol MIC results suggestive of a resistant interpretive category should be submitted to a reference laboratory for further testing. Table 4. Performance of Enterobacteriaceae Clinical and Challenge Isolates, Read Using VIZION | | Tot | EA N | EA % | Eval Tot | Eval EA N | Eval EA % | CA Tot | CA % | No. R | No. S | Min | maj | vmj | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Enterobacteriaceae a, ≤2(S), 4(I), ≥8 (R) | | | | | | | | | | | | | | | Clinical | 268 | 253 | 94.4 | 195 | 180 | 92.3 | 258 | 96.3 | 7 | 250 | 10 | 0 | 0 | | Challenge | 82 | 75 | 91.5 | 69 | 62 | 89.9 | 64 | 78.0 | 25 | 41 | 17 | 0 | 1 | | Total | 350 | 328 | 93.7 | 264 | 242 | 91.7 | 322 | 92.0 | 32 | 291 | 27 | 0 | 1 | aIncludes *E. coli*, *E. cloacae*, *K. pneumoniae* and *P. mirabilis* EA – Essential Agreement (+/- 1 dilution) CA – Category Agreement EVAL – Evaluable isolates R – Resistant isolates min – minor discrepancies maj – major discrepancies vmj – very major discrepancies Essential agreement (EA) occurs when the result of the reference method and that of the Sensititre panel 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 Sensititre panel. Category agreement (CA) occurs when the interpretation of the result of the reference method agrees exactly with the interpretation of the Sensititre panel. Table 5. Performance of Enterobacteriaceae Clinical and Challenge Isolates, Read Using OptiRead | | Tot | EA N | EA % | Eval Tot | Eval EA N | Eval EA % | CA Tot | CA % | No. R | No. S | Min | maj | vmj | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Enterobacteriaceae a, ≤2(S), 4(I), ≥8 (R) | | | | | | | | | | | | | | | Clinical | 268 | 250 | 93.3 | 193 | 175 | 90.7 | 258 | 96.3 | 7 | 250 | 10 | 0 | 0 | | Challenge | 82 | 75 | 91.5 | 69 | 62 | 89.9 | 59 | 72.0 | 25 | 41 | 22 | 0 | 1 | | Total | 350 | 325 | 92.9 | 262 | 237 | 90.5 | 317 | 90.6 | 32 | 291 | 32 | 0 | 1 | aIncludes *E. coli*, *E. cloacae*, *K. pneumoniae* and *P. mirabilis* Table 6. Performance of *P. aeruginosa* Clinical and Challenge Isolates, Read Using VIZION | | Tot | EA N | EA % | Eval Tot | Eval EA N | Eval EA % | CA Tot | CA % | No. R | No. S | Min | maj | vmj | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | P. aeruginosa, ≤1(S), 2(I), ≥4 (R) | | | | | | | | | | | | | | | Clinical | 60 | 58 | 96.7 | 58 | 56 | 96.6 | 59 | 98.3 | 0 | 58 | 1 | 0 | 0 | | Challenge | 21 | 21 | 100 | 21 | 21 | 100 | 18 | 85.7 | 0 | 20 | 3 | 0 | 0 | | Total | 81 | 79 | 97.5 | 79 | 77 | 97.5 | 77 | 94.8 | 0 | 78 | 4 | 0 | 0 | Table 7. Performance of *P. aeruginosa* Clinical and Challenge Isolates, Read Using OptiRead | | Tot | EA N | EA % | Eval Tot | Eval EA N | Eval EA % | CA Tot | CA % | No. R | No. S | Min | maj | vmj | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | P. aeruginosa, ≤1(S), 2(I), ≥4 (R) | | | | | | | | | | | | | | | Clinical | 60 | 58 | 96.7 | 59 | 57 | 96.6 | 58 | 96.7 | 0 | 58 | 2 | 0 | 0 | | Challenge | 21 | 21 | 100 | 21 | 21 | 100 | 17 | 81.0 | 0 | 20 | 4 | 0 | 0 | | Total | 81 | 79 | 97.5 | 80 | 78 | 97.5 | 75 | 92.6 | 0 | 78 | 6 | 0 | 0 | Resistance Mechanisms K193538 - Page 9 of 12 {9} Challenge isolates of Enterobacteriaceae harboring various molecular mechanisms of resistance noted in the FDA drug label were tested with cefiderocol. The following resistance mechanisms were evaluated: ESBLs (TEM, SHV, CTX-M, oxacillinase [OXA]), AmpC, AmpC-type ESBL (CMY), serine carbapenemases (such as KPC, OXA-48), and metallo-carbapenemases (such as NDM and VIM) and OmpK35/36 porin deletion. ## MIC Trending An analysis of trending was conducted using the combined clinical and challenge data 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 compared to the reference method irrespective of whether the device MIC values are on-scale or not. Trending results are shown in Table 8 for Enterobacteriaceae and for *P. aeruginosa* in Table 9. Results for Enterobacteriaceae were also stratified by species to determine if particular trends were observed. The acceptable percent difference between higher and lower dilution readings is <30%. Table 8. Trending in Enterobacteriaceae, Clinical and Challenge Isolates | Organism (Read Method) | Total evaluable for trending | ≥1 dilution lower No. (%) | Exact No (%) | ≥1 dilution higher No (%) | Percent Difference (CI) | Trending Noted | | --- | --- | --- | --- | --- | --- | --- | | E.coli (VIZION) | 93 | 47 (50.5) | 28 (30.1) | 18 (19.4) | -31.2 (-43.2 to -17.6) | Yes | | E.coli (OptiRead) | 93 | 51 (54.8) | 26 (28.0) | 16 (17.2) | -37.6 (-49.2 to -24.2) | Yes | | E. cloacae (VIZION) | 87 | 34 (39.1) | 34 (39.1) | 19 (21.8) | -17.2 (-30.1 to -3.6) | No | | E. cloacae (OptiRead) | 86 | 40 (46.5) | 32 (37.2) | 14 (16.3) | -30.2 (-42.5 to -16.5) | Yes | | K. pneumoniae (VIZION) | 98 | 35 (35.7) | 39 (39.8) | 24 (24.5) | -17.2 (-29.5 to -4.2) | No | | K. pneumoniae (OptiRead) | 96 | 45 (46.9) | 30 (31.2) | 21 (21.9) | -25.0 (-37.2 to -11.6) | No | | P. mirabilis (VIZION) | 10 | 5 (50.0) | 3 (30.0) | 2 (20.0) | -30.0 (-60.0 to 10.7) | Yes | | P. mirabilis (OptiRead) | 10 | 5 (50.0) | 3 (30.0) | 2 (20.0) | -30.0 (-60.0 to 10.7) | Yes | | Enterobacteriaceae (VIZION) | 288 | 121 (42.0) | 104 (36.1) | 63 (21.9) | -20.1 (-27.4 to -12.6) | No | | Enterobacteriaceae (OptiRead) | 285 | 141 (49.5) | 91 (31.9) | 53 (18.6) | -30.9 (-38.0 to -23.3) | Yes | Table 9. Trending in *P. aeruginosa*, Clinical and Challenge Isolates | Organism (Read Method) | Total evaluable for trending | ≥1 dilution lower No. (%) | Exact No (%) | ≥1 dilution higher No (%) | Percent Difference (CI) | Trending Noted | | --- | --- | --- | --- | --- | --- | --- | | P. aeruginosa (VIZION) | 80 | 13 (16.3) | 39 (48.8) | 28 (35.0) | 18.8 (5.2 to 31.5) | No | | P. aeruginosa (OptiRead) | 81 | 9 (11.1) | 37 (45.7) | 35 (43.2) | 32.1 (18.7 to 44.1) | Yes | K193538 - Page 10 of 12 {10} A trend toward lower MIC readings was observed for E. coli and P. mirabilis with both VIZION and OptiRead. A trend toward lower MIC readings was observed for E. cloacae for OptiRead; a trend toward higher MIC readings was observed for P. aeruginosa for OptiRead. The sponsor included the following footnotes to the performance table to address the trending observed with Cefiderocol: Cefiderocol MIC values tended to be in exact agreement or at least one dilution higher when testing P. aeruginosa with OptiRead compared to the CLSI reference broth microdilution. MIC values tended to be in exact agreement or one dilution lower when testing E. coli, P. mirabilis and E. cloacae. Cefiderocol MIC values tended to be in exact agreement or at least one dilution lower when testing E. coli and P. mirabilis with VIZION compared to the CLSI reference broth microdilution. 2. Matrix Comparison: Not applicable C Clinical Studies: 1. Clinical Sensitivity: Not applicable 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: The FDA-identified susceptibility interpretative criteria for Cefiderocol are listed in Table 10. Table 10: FDA-Identified Interpretative Criteria ${}^{a}$ for Cefiderocol $\left( {\mu \mathrm{g}/\mathrm{{mL}}}\right)$ | | Susceptible (S) | Intermediate (I) | Resistant (R) | | --- | --- | --- | --- | | Enterobacteriaceaeb | ≤2 | 4 | ≥8 | | Pseudomonas aeruginosa | ≤1 | 2 | ≥4 | aFDA STIC Webpage bIncludes Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis and Enterobacter cloacae complex VIII Proposed Labeling: The labeling supports the finding of substantial equivalence for this device. IX Conclusion: K193538 - Page 11 of 12 {11} 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 ThermoFisher intends to use to evaluate the Sensititre 18-24 hour MIC or Breakpoint Susceptibility System with Cefiderocol in the dilution range of 0.03 – 64 µg/mL when revised breakpoints for cefiderocol are published on the FDA STIC webpage. The breakpoint change protocol included with the submission indicated that if specific criteria are met, ThermoFisher will update the cefiderocol 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. K193538 - Page 12 of 12