SENSITITRE 18-24 HOUR SUSCEPTIBILITY PLATES

K142151 · Thermo Fisher Scientific · JWY · Dec 23, 2014 · Microbiology

Device Facts

• Record ID: K142151
• Device Name: SENSITITRE 18-24 HOUR SUSCEPTIBILITY PLATES
• Applicant: Thermo Fisher Scientific
• Product Code: JWY · Microbiology
• Decision Date: Dec 23, 2014
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 866.1640
• Device Class: Class 2

Indications 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.

Device Story

Sensititre 18-24 hour MIC or Breakpoint Susceptibility System; micro-broth dilution method for antimicrobial susceptibility testing (AST). Dried microtitre plates pre-dosed with antimicrobial agents (Tedizolid 0.03-4μg/mL). Pure culture isolates inoculated into plates; incubated 18-24 hours. Bacterial growth detected via fluorescence of surface enzymes acting on fluorogenic substrate. Results read manually (VIZION) or automatically (OptiRead). Provides Minimum Inhibitory Concentration (MIC) and interpretative criteria (SIR). Used in clinical labs to guide antibiotic selection for S. aureus and E. faecalis infections.

Clinical Evidence

Bench testing only. Performance was evaluated by comparing the Sensititre system's MIC results for Tedizolid against a reference broth microdilution method. Testing included clinical isolates of Staphylococcus aureus and Enterococcus faecalis. Results demonstrated essential agreement and categorical agreement within acceptable FDA criteria for antimicrobial susceptibility testing devices.

Technological Characteristics

Multi-well plastic microtitre plates; dried antimicrobial agents. Sensing principle: fluorescence detection of bacterial surface enzyme activity on fluorogenic substrate. Connectivity: OptiRead (automated) or VIZION (manual). Software: automated reading algorithm. Sterilization: not specified.

Indications for Use

Indicated for clinical susceptibility testing of non-fastidious gram-positive isolates, specifically Staphylococcus aureus (MRSA and MSSA) and Enterococcus faecalis.

Regulatory Classification

Identification

An antimicrobial susceptibility test powder is a device that consists of an antimicrobial drug powder packaged in vials in specified amounts and intended for use in clinical laboratories for determining in vitro susceptibility of bacterial pathogens to these therapeutic agents. Test results are used to determine the antimicrobial agent of choice in the treatment of bacterial diseases.

Predicate Devices

• Sensititre 18-24 hour MIC or Breakpoint Susceptibility System (K142151)

Submission Summary (Full Text)

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# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY ASSAY ONLY TEMPLATE

A. 510(k) Number:
k142151

B. Purpose for Submission:
Addition of Tedizolid to the Sensititre 18-24 hour susceptibility plates

C. Measurand:
Tedizolid 0.03- 4μg/mL

D. Type of Test:
Quantitative Antimicrobial Susceptibility Test (AST) growth based

E. Applicant:
ThermoFisher Scientific

F. Proprietary and Established Names:
Sensititre 18-24 hour Susceptibility plates

G. Regulatory Information:

1. Regulation section:
21 CFR 866.1640 Antimicrobial Susceptibility Test Powder

2. Classification:
Class II

3. Product code:
JWY- Manual Antimicrobial Test
LRG- Instrument for Auto Reader and Instrumentation of Overnight Susceptibility Systems
LTT- Panels, Test, Susceptibility, Antimicrobial

4. Panel:

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83. Microbiology

H. Intended Use:

1. Intended use(s):

The Sensititre 18-24 hour MIC or Breakpoint Susceptibility System is an *in vitro* diagnostic product for clinical susceptibility testing of non-fastidious isolates.

2. 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 the newly approved Tedizolid in the dilution range of 0.03- 4µg/mL for testing non-fastidious gram positive organisms on the Sensititre 18-24hour MIC panel.

The approved primary “Indications for Use” and clinical significance for non-fastidious gram positive isolates:

*Staphylococcus aureus* (including methicillin-resistant [MRSA] and methicillin-susceptible [MSSA] isolates)
*Enterococcus faecalis*

3. Special conditions for use statement(s):

For prescription use only

4. Special instrument requirements:

Sensititre OptiRead System for automatic read
Sensititre VIZION for manual visual read

The ability of the Sensititre system to detect non-susceptible or resistant isolates to tedizolid is unknown because neither non-susceptible nor resistant isolates were available at the time of the comparative testing. If such isolates are observed, they should be submitted to a reference lab.

I. Device Description:

The Sensititre 18-24 hour MIC or Breakpoint Susceptibility System is a micro-version of the classic broth dilution method and can provide both qualitative and quantitative susceptibility test results in a dried microtitre plate format. Each micro-broth dilution plate is dosed with antimicrobial agents as specific concentrations and then dried.

The organism to be tested must be in pure culture and identified as Gram negative. A standardized suspension is prepared from colonies in pure growth and inoculated into the

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microtitre plate. After the indicated hours of incubation, the microtitre plate is examined for growth to determine the MIC using either the Sensititre OptiRead or manually using the VIZION.

# J. Substantial Equivalence Information:

1. Predicate device name(s):

MicroScan Dried Gram-Negative and Gram-Positive MIC Combo Panels

2. Predicate $510(\mathbf{k})$ number(s):

k010159

3. Comparison with predicate:

Table 1: Comparison with the Predicate Device

| Similarities | | |
| --- | --- | --- |
| Item | Device Sensititre 18-24 hour Susceptibility plates S. aureus, E. faecalis Tedizolid | Predicate MicroScan® Dried Gram-Negative and Gram-Positive MIC Combo Panels K010159 |
| Intended Use | The Sensititre MIC or Breakpoint Susceptibility system is an in vitro diagnostic product for clinical susceptibility testing | Same |
| Test organism | Non-fastidious gram positive isolates from culture | Same |
| Results reported | Report results as Minimum Inhibitory Concentration (MIC) and interpretative criteria (SIR) | Same |
| Type of Test | Automatic or Manual | Same |
| Differences | | |
| --- | --- | --- |
| Item | Device | Predicate |
| Incubation | 18-24 hours | 16-20 hours |
| Antibiotic | Tedizolid | Gatifloxacin |
| Reading method | Automated OptiRead by detection of fluorescence. Manual method by visual read of growth | Organism growth read visually or by MicroScan instrumentation |

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K. Standard/Guidance Document Referenced (if applicable):

1. Class II Special Controls Guidance Document: Antimicrobial Susceptibility Test Systems; Guidance for Industry and FDA5
2. CLSI M100-S24: Performance Standards for Antimicrobial Susceptibility Testing; Twenty-fourth Informational Supplement (QC parameters only)
3. CLSI M7-A9: Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard- Ninth Edition

L. Test Principle:

The Sensititre 18-24 MIC Susceptibility System test panels are multi-well plastic microtitre plates that contain doubling dilution of antibacterial agents. Each plate includes antimicrobial agents at appropriate dilutions. Results can be read manually by visual reading of growth or automatically on an autoreader via fluorescence.

The Sensititre AutoReader /OptiRead System 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 non-fluorescent (fluorogenic) substrate. The non-fluorescent 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 bound non-fluorescent substrate cleaves the bond releasing the fluorescence. The amount of fluorescence detected is directly related to the activity of bacterial growth. The MIC is determined by observing the lowest dilution of antimicrobial agent that inhibits growth of the organism. The non-fluorescent (fluorogenic) 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.

M. Performance Characteristics (if/when applicable):

1. Analytical performance:

a. Precision/Reproducibility:

Reproducibility study was performed using 25 strains of MSSA, MRSA and Enterococcus faecalis. The Sensititre plates were inoculated by the Sensititre Autoinoculator/AIM. The organisms were tested one time at each of three sites for each reading method (Vizion for manual, OptiRead for automated read). The mode MIC value was determined and the reproducibility was calculated based on MICs falling within ± 1 dilution of the mode MIC value. The testing resulted in overall reproducibility results of greater than 95% for both manual and automated read methods. The results were acceptable.

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b. Linearity/assay reportable range:

Not Applicable

c. Traceability, Stability, Expected values (controls, calibrators, or methods):

Organisms recommended by both the FDA (CDER) and the CLSI, namely Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 29212 were tested against Tedizolid. Quality control was performed at all sites using the Sensititre Autoinoculator/AIM for inoculation, read by the manual (i.e. Vizion) and the automated (i.e. OptiRead) read methods. The following table represents the frequency of the results and all results were in acceptable range.

Table 2: Tedizolid QC results by Sensititre auto and manual reads

| ORGANISM | Conc. (μg/mL) | Reference | Sensititre Auto Read (OptiRead) | Sensititre Manual (Vizion) |
| --- | --- | --- | --- | --- |
| | | | | |
| S. aureus ATCC29213 Expected Range 0.25- 1μg/mL | 0.12 | | | |
| | 0.25 | 41 | 45 | 46 |
| | 0.5 | 17 | 15 | 12 |
| | 1 | 2 | | 2 |
| | 2 | | | |
| | | | | |
| E. faecalis ATCC29212 Expected Range 0.25- 1μg/mL | 0.12 | | | |
| | 0.25 | 38 | 58 | 30 |
| | 0.5 | 21 | 2 | 30 |
| | 1 | 1 | | |
| | 2 | | | |

The inoculum density of the quality control organisms was determined each day of testing. A total of 97 inoculum density checks were performed; the average colony counts of each QC strain at each site were within the recommended range.

d. Detection limit:

Not Applicable

e. Analytical specificity:

Not Applicable

f. Assay cut-off:

Not Applicable

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# 2. Comparison studies:

# a. Method comparison with predicate device:

The CLSI recommended broth microdilution reference plate was prepared according to CLSI recommendation. Clinical testing was performed on 330 Staphylococcus aureus, 60 Enterococcus faecalis at three sites and Sensititre AIM autoinoculator was used as the inoculation method. For Staphylococcus aureus clinical isolates, there were 165 each for MRSA and MSSA. They were all fresh isolates. The no growth/insufficient fluorescent signal rate was $0.52\%$ (2/390) in the automated read method; they all grew in the manual VIZION read method. The challenge set included 75 Staphylococcus aureus and 17 Enterococcus faecalis. The performance of Staphylococcus aureus is shown in the tables below.

Table 3: Performance summary of Staphylococcus aureus - Manual Read (Vizion)

| Tedizolid | EA Tot | EA N | EA % | Eval EA Tot | Eval EA N | Eval EA % | CA N | CA% | #R | min | maj | vmj |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | MRSA (≤0.5, 1, ≥2) | | | | | | | | | | | |
| Clinical | 165 | 165 | 100 | 165 | 165 | 100 | 165 | 100 | 0 | 0 | 0 | 0 |
| Challenge | 38 | 38 | 100 | 38 | 38 | 100 | 38 | 100 | 0 | 0 | 0 | 0 |
| Total | 203 | 203 | 100 | 203 | 203 | 100 | 203 | 100 | 0 | 0 | 0 | 0 |
| | MSSA (≤0.5, 1, ≥2) | | | | | | | | | | | |
| Clinical | 165 | 165 | 100 | 165 | 165 | 100 | 164 | 99.4 | 0 | 1 | 0 | 0 |
| Challenge | 37 | 37 | 100 | 37 | 37 | 100 | 37 | 100 | 0 | 0 | 0 | 0 |
| Total | 202 | 202 | 100 | 202 | 202 | 100 | 201 | 99.5 | 0 | 1 | 0 | 0 |
| S. aureus | 405 | 405 | 100 | 405 | 405 | 100 | 404 | 99.8 | 0 | 1 | 0 | 0 |

EA - Essential Agreement
CA - Category Agreement
R- resistant isolates

maj - major discrepancies
vmj- very major discrepancies
min- minor discrepancies

EA is when there is agreement between the reference method and the Sensititre panel within plus or minus one serial two-fold dilution of antibiotic. Category agreement (CA) is when the Sensititre panel result interpretation agrees exactly with the reference panel result interpretation. Evaluable EA is when the MIC result is on scale for both the Sensititre and the reference and have on-scale EA. The $\mathrm{EA\%}$ is acceptable when compared to the reference method as described in the FDA guidance document, "Class II Special Controls Guidance Document: Antimicrobial Susceptibility Test (AST) Systems; Guidance for Industry and FDA".

Table 4: Performance summary of Staphylococcus aureus - Automated Read (OptiRead)

| Tedizolid | EA Tot | EA N | EA % | Eval EA Tot | Eval EA N | Eval EA % | CA N | CA% | #R | min | maj | vmj |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | MRSA (≤0.5, 1, ≥2) | | | | | | | | | | | |
| Clinical | 165 | 164 | 99.4 | 165 | 164 | 99.4 | 165 | 100 | 0 | 0 | 0 | 0 |
| Challenge | 38 | 38 | 100 | 38 | 38 | 100 | 38 | 100 | 0 | 0 | 0 | 0 |
| Total | 203 | 202 | 99.5 | 203 | 202 | 99.5 | 203 | 100 | 0 | 0 | 0 | 0 |
| | MSSA (≤0.5, 1, ≥2) | | | | | | | | | | | |
| Clinical | 163 | 163 | 100 | 163 | 163 | 100 | 162 | 99.4 | 0 | 1 | 0 | 0 |
| Challenge | 37 | 37 | 100 | 37 | 37 | 100 | 37 | 100 | 0 | 0 | 0 | 0 |
| Total | 200 | 200 | 100 | 200 | 200 | 100 | 199 | 99.5 | 0 | 1 | 0 | 0 |
| S. aureus | 403 | 402 | 99.8 | 403 | 402 | 99.8 | 402 | 99.8 | 0 | 1 | 0 | 0 |

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The EA% is acceptable when compared to the reference method as described in the FDA guidance document, "Class II Special Controls Guidance Document: Antimicrobial Susceptibility Test (AST) Systems; Guidance for Industry and FDA".

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.

## MRSA

A trending was observed at the susceptible breakpoint (BP) of 0.5μg/mL on the automated reading method. There were a total of 26 isolates at this susceptible BP by the automated read, and 20 were one to two doubling dilutions lower than the reference method, a rate of 76.9% (20/26). Nineteen were within EA. Using the manual read with VIZION, there were eight (8) results that were one dilution lower than results obtained with the reference method, a rate of 29.6% (8/27). They all were within EA. No isolates were at the non-susceptible (i.e. intermediate or resistant) range in the comparative study.

## MSSA

At the BP of 0.5μg/mL, there were 23 results (50%, 23/46) that were one doubling dilution lower than results obtained with the automated reading method and seven results (13.7%, 7/51) that were lower with the manual VIZION method. There was one result in the intermediate range that was also one doubling dilution lower. There were no results in the resistant range.

At the susceptible (0.5μg/mL) BP, the following is footnoted in the "Performance Characteristics of Sensititre Panels Read at 18-24 hours on Optiread" section of the Addendum to Technical Product Information:

"Staphylococcus aureus (MRSA and MSSA) MIC values tended to be one doubling dilution lower at the susceptible (0.5μg/mL) breakpoints"

The performance of Enterococcus faecalis is shown below.

Table 5: Performance summary of Enterococcus faecalis (≤0.5,--, --) Manual (Vizion)

| Tedizolid | EA Tot | EA N | EA % | Eval EA Tot | Eval EA N | Eval EA % | CA N | CA % | #NS |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Clinical | 60 | 60 | 100 | 60 | 60 | 100 | 60 | 100 | 0 |
| Challenge | 17 | 17 | 100 | 17 | 17 | 100 | 17 | 100 | 0 |
| Total | 77 | 77 | 100 | 77 | 77 | 100 | 77 | 100 | 0 |

EA - Essential Agreement
CA - Category Agreement
NS - Not susceptible

Table 6: Performance summary of Enterococcus faecalis (≤0.5,--, --) automated (Optiread)

| Tedizolid | EA Tot | EA N | EA % | Eval EA Tot | Eval EA N | Eval EA % | CA N | CA % | #NS |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Clinical | 60 | 59 | 98.3 | 60 | 59 | 98.3 | 60 | 100 | 0 |
| Challenge | 17 | 17 | 100 | 17 | 17 | 100 | 17 | 100 | 0 |
| Total | 77 | 76 | 98.7 | 77 | 76 | 98.7 | 77 | 100 | 0 |

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Table 7: Trending comparison between VIZON and OptiRead for Enterococcus faecalis (clinical +challenge)

| Tedizolid | Total | ≥1 dil. lower | Exact | ≥1 dil. higher |
| --- | --- | --- | --- | --- |
| Manual (Vizion) | 77 | 3.9% (3/77) | 63.6% (49/77) | 32.5% (25/77) |
| Automated (Optiread) | 77 | 37.7% (29/77) | 55.8% (43/77) | 6.5% (5/77) |

Enterococcus faecalis

The clinical data demonstrated a trending of one dilution higher 32.5% (25/77) on the manual read. However, it was one doubling dilution lower 37.7% (29/77) on the automated read. The "exact" reading compared to the reference was similar, 63.6% (49/77) for the manual and 55.8% (43/77) for the automated.

There were a total of ten isolates with results at the BP of 0.5μg/mL. There was one result that was one doubling lower than the reference on the manual read. However, six results (60%, 6/10) were one doubling lower in the automated read. In general, results were one doubling dilution lower on the automated read.

The following is footnoted in "Performance Characteristics of Sensititre Panels Read at 18-24 hours" section of the Addendum to Technical Product Information:

"Sensititre Tedizolid MIC values for Enterococcus faecalis tended to be one doubling dilution higher than the reference MIC values on the manual VIZION read."

"On the Optiread read, Sensititre Tedizolid MIC values tended to be one doubling dilution lower than the reference MIC values for Enterococcus faecalis;"

Table 8: Performance of Staphylococcus aureus and Enterococcus faecalis combined

| Tedizolid | EA Tot | EA % | EA % | Eval EA Tot | Eval EA % | Eval EA % | CA % | CA % | #R | min | maj | vmj |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | Manual | | | | | | | | | | | |
| S. aureus | 405 | 405 | 100 | 405 | 405 | 100 | 404 | 99.8 | 0 | 1 | 0 | 0 |
| E. faecalis | 77 | 77 | 100 | 77 | 77 | 100 | 77 | 100 | 0 | NA | NA | NA |
| Total | 482 | 482 | 100 | 482 | 482 | 100 | 481 | 99.8 | 0 | 1 | 0 | 0 |
| | Automated | | | | | | | | | | | |
| S. aureus | 403 | 402 | 99.8 | 403 | 402 | 99.8 | 402 | 99.8 | 0 | 1 | 0 | 0 |
| E. faecalis | 77 | 76 | 98.7 | 77 | 76 | 98.7 | 77 | 100 | 0 | NA | NA | NA |
| Total | 480 | 478 | 99.6 | 480 | 478 | 99.6 | 479 | 99.8 | 0 | 1 | 0 | 0 |

b. Matrix comparison:

Not Applicable

3. Clinical studies:

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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:

Tedizolid Interpretative Criteria:

S. aureus (MRSA, MSSA) ≤0.5(S), 1(I), ≥2(R)

E. faecalis ≤0.5(S), --, --

The FDA interpretative criteria, as listed above, were used to evaluate all performance data.

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.