← Product Code [JWY](/submissions/MI/subpart-b%E2%80%94diagnostic-devices/JWY) · K182797

# Sensititre 18-24 hour MIC or Breakpoint Susceptibility System with Eravacycline in the dilution range of 0.008- 16 µg/mL (K182797)

_Thermo Fisher Scientific · JWY · Nov 30, 2018 · Microbiology · SESE_

**Canonical URL:** https://fda.innolitics.com/submissions/MI/subpart-b%E2%80%94diagnostic-devices/JWY/K182797

## Device Facts

- **Applicant:** Thermo Fisher Scientific
- **Product Code:** [JWY](/submissions/MI/subpart-b%E2%80%94diagnostic-devices/JWY.md)
- **Decision Date:** Nov 30, 2018
- **Decision:** SESE
- **Submission Type:** Traditional
- **Regulation:** 21 CFR 866.1640
- **Device Class:** Class 2
- **Review Panel:** Microbiology

## 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 spp., Enterococcus spp., and Beta haemolytic Streptococci other than S. pneumoniae.

## Device Story

Sensititre 18–24 hour MIC or Breakpoint Susceptibility System uses multi-well plastic micro-titer plates dosed with dried, stabilized antimicrobials; miniaturized broth dilution method. Inoculated plates are incubated (34–36°C) for 18–24 hours. Bacterial growth is detected via surface enzyme activity using a fluorogenic substrate; fluorescence intensity correlates with growth. Plates are read using either the VIZION digital viewing device (manual selection) or the OptiRead automated reader (fluorescence detection). Used in clinical microbiology laboratories by technicians. Output is the Minimum Inhibitory Concentration (MIC) and interpretive category (Susceptible). Results assist clinicians in selecting appropriate antimicrobial therapy for bacterial infections. Benefits include standardized, quantitative susceptibility testing to guide antibiotic treatment.

## Clinical Evidence

No clinical data provided in the document; substantial equivalence is based on bench testing and performance characteristics of the antimicrobial susceptibility test system.

## Technological Characteristics

Multi-well plastic micro-titer plates; dried, stabilized antimicrobial agents. Sensing principle: fluorescence detection of bacterial surface enzyme activity. Dimensions: 96-well format. Connectivity: standalone (VIZION) or instrument-integrated (OptiRead). Sterilization: not specified. Software: automated reading algorithm for fluorescence quantification.

## Regulatory 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.

## Submission Summary (Full Text)

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

A. 510(k) Number:
K182797

B. Purpose for Submission:
To obtain a substantial equivalence determination for the addition of Eravacycline at concentrations 0.008 – 16 µg/mL for testing non-fastidious Gram negative and Gram positive organisms on the Sensititre 18 – 24 hour MIC or Breakpoint Susceptibility System

C. Measurand:
Eravacycline 0.008 – 16 µg/mL

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

E. Applicant:
ThermoFisher Scientific

F. Proprietary and Established Names:
Sensititre 18 24 hour MIC or Breakpoint Susceptibility System with Eravacycline in the dilution range of 0.008 – 16 µg/mL

G. Regulatory Information:
1. Regulation section:
866.1640 Antimicrobial Susceptibility Test Powder
2. Classification:
Class II
3. Product code:
JWY- Manual Antimicrobial Susceptibility Test Systems
LRG- Instrument for Auto Reader and Instrumentation of Overnight Susceptibility Systems

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LTT- Panels, Test, Susceptibility, Antimicrobial

4. Panel:
83- Microbiology

H. Intended Use:

1. 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 haemolytic Streptococci other than S. pneumoniae.

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 Eravacycline in the dilution range 0.008 – 16 µg/mL for testing non-fastidious Gram negative and Gram positive organisms on the Sensititre 18 – 24 hour MIC panel.

Eravacycline 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
- Klebsiella oxytoca
- Klebsiella pneumoniae
- Citrobacter freundii
- Enterobacter cloacae

- Gram positive bacteria
- Enterococcus faecalis
- Enterococcus faecium
- Staphylococcus aureus

The following in vitro data are available, but their clinical significance is unknown:

- Gram negative bacteria
- Citrobacter koseri
- Klebsiella (Enterobacter) aerogenes

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3. Special conditions for use statement(s):

For prescription use only

The following information is included in the limitation section of the labeling:

**Non-Fastidious Gram Negative Organisms:**

- The performance of eravacycline with Gram negative organisms was performed using the AutoReader (OptiRead) and VIZION reading methods only. The use of an alternative reading method when testing eravacycline has not been evaluated.
- Studies of eravacycline were performed using the AIM autoinoculator. The use of an alternative inoculation system when testing eravacycline has not been evaluated.
- There were 47 Eravacycline non-susceptible *Enterobacteriaceae* isolates as determined by the reference method. Although MIC results were within essential agreement, five and six potential very major (vmj) discrepancies were observed with the VIZION and OptiRead, respectively, due to the lack of intermediate category. When the Sensititre MIC is at the breakpoint of 0.5 µg/mL, testing should be repeated using a reference/alternative testing method prior to reporting results for Eravacycline with *Enterobacter cloacae*, *E. coli*, *K. pneumoniae*, or *Citrobacter koseri* with VIZION and *Enterobacter cloacae*, *E. coli*, *K. pneumoniae*, *K. oxytoca*, or *Citrobacter koseri* with OptiRead.
- Resistance mechanism characterization was not available for all organisms at the time of comparative testing, and therefore the performance of the Sensititre Eravacycline is unknown for *Enterobacteriaceae* with efflux mediated by tet(A), and tet(B).
- The safety and efficacy of eravacycline in treating clinical infections due to bacteria other than *E. coli*, *K. pneumoniae*, *K. oxytoca*, *E. cloacae*, and *C. freundii* may or may not have been established in adequate and well-controlled clinical trials and the clinical significance of such susceptibility information in those instances is unknown.

**Non-Fastidious Gram Positive Organisms (*Staphylococcus aureus*, *Enterococcus faecalis*, *E. faecium*):**

- Studies of Eravacycline were performed using the AIM autoinoculator. The use of an alternative inoculation system when testing Eravacycline has not been evaluated.
- The performance of Eravacycline with *Staphylococcus aureus* (MRSA and MSSA), *Enterococcus faecalis*, and *Enterococcus faecium* was evaluated using

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the AutoReader (OptiRead) and Vizion reading methods only. The use of an alternative reading method when testing Eravacycline has not been evaluated.

- There were 561 Eravacycline susceptible Gram positive (non-fastidious) isolates as determined by the reference method. Although within essential agreement, 39 and 24 potential major (maj) discrepancies were observed with the VIZION and OptiRead, respectively, due to the lack of an intermediate category. When the Sensititre MIC is at 0.12 µg/mL, the non-susceptible breakpoint, testing should be repeated using a reference/alternative testing method prior to reporting results for Eravacycline with S. aureus, E. faecalis, and E. faecium for the VIZION reading method and S. aureus with the OptiRead reading method.

- There were 41 Eravacycline non-susceptible Gram positive (non-fastidious) isolates as determined by the reference method. Although within essential agreement, four and five potential very major (vmj) discrepancies were observed with the VIZION and OptiRead, respectively, due to the lack of intermediate category. When the Sensititre MIC is at the breakpoint of 0.06 µg/mL, testing should be repeated using a reference/alternative testing method prior to reporting results for Eravacycline with Staphylococcus aureus with VIZION and with OptiRead.

- Resistance mechanism characterization was not available for all organisms at the time comparative testing, and therefore the performance of the Sensititre Eravacycline is unknown for non-fastidious Gram positive (Staphylococcus aureus, Enterococcus faecalis, and Enterococcus faecium) isolates with efflux mediated by tet(K) and ribosomal protection as encoded by tet(M).

- The safety and efficacy of eravacycline in treating clinical infections due to bacteria other than Staphylococcus aureus, Enterococcus faecalis, and Enterococcus faecium may or may not have been established in adequate and well-controlled clinical trials and the clinical significance of such susceptibility information in those instances is unknown.

4. Special instrument requirements:

- Sensititre AIM for device inoculation
- Sensititre VIZION or OptiRead for plate reading

I. Device Description:

Sensititre MIC Susceptibility plate MIC panels are multi-well plastic micro-titer plates, dosed with dried, stabilized antimicrobials. It is a miniaturized version of the classic broth dilution methods 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.

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Antimicrobial susceptibility test results can be determined by reading of growth using the digital viewing device (VIZION) or automatically on an autoreader (OptiRead) using fluorescence.

# J. Substantial Equivalence Information:

1. Predicate device name(s):

Sensititre 18-24 hour Susceptibility MIC Plates, Ceftazidime/avibactam

2. Predicate 510(k) number(s):

K152774

3. Comparison with predicate:

Table 1: Comparison with Predicate Device

|  Similarities  |   |   |
| --- | --- | --- |
|  Item | Device Sensititre 18-24 Susceptibility System, Eravacycline (K182797) | Predicate Sensititre 18-24 Susceptibility System, Ceftazidime/avibactam (K152774)  |
|  Intended 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 spp., Enterococcus spp., and Beta haemolytic Streptococci other than S. pneumoniae | Same  |
|  Test Panel | 96-well plate dosed with selected antimicrobial agents then dried | Same  |
|  Reading Methods | Results can be read by 1) the automated OptiRead, 2) the digital viewing VIZION device | Same  |
|  Incubation | 18 – 24 hours | Same  |
|  Differences  |   |   |
|  Drug | Eravacycline | Ceftazidime/Avibactam  |
|  Dilutions | 0.008 – 16 μg/mL for Gram negative and Gram positive isolates | 0.015/4 – 32/4 μg/mL for Gram negative isolates  |

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|  Similarities  |   |   |
| --- | --- | --- |
|  Item | Device
Sensititre 18–24 Susceptibility System,
Eravacycline
(K182797) | Predicate
Sensititre 18–24 Susceptibility System,
Ceftazidime/avibactam
(K152774)  |
|  |   |   |
|  Results | Report results as Minimum Inhibitory Concentration (MIC) and interpretive criteria (S, --, --).
Susceptible is the only interpretive category for Eravacycline | Report results as Minimum Inhibitory Concentration (MIC) and interpretive criteria (S, I, R)  |

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

Guidance for Industry and FDA - Class II Special Controls Guidance Document: Antimicrobial Susceptibility Test (AST) Systems – August 28, 2009.

CLSI M100: Performance Standards for Antimicrobial Susceptibility Testing; 28th Edition, January 2018

CLSI M7: Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically, 11th Edition, January 2018

L. Test Principle:

The Sensititre 18 - 24 hour MIC or Breakpoint Susceptibility System are multi-well plastic microtitre plates that contain doubled dilution of antibacterial agents. Each plate includes antimicrobial agents at appropriate dilutions. Results can be read by the 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 manually select 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.

M. Performance Characteristics (if/when applicable):

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1. Analytical performance:

a. Precision/Reproducibility:

**Non-fastidious Gram Negative Organisms**

A reproducibility study was performed at four sites using 12 Gram negative organisms that included five *E. coli* isolates, four *Klebsiella pneumoniae* isolates, two isolates of *K. oxytoca*, and one *Enterobacter cloacae* isolate. The isolates were tested in triplicate over three different days for each reading method (i.e., VIZION and OptiRead) for a total of 432 data points for each.

**Non-fastidious Gram Positive Organisms**

A reproducibility study was performed at four sites using 13 Gram positive organisms that included five methicillin resistant *Staphylococcus aureus* (MRSA), five methicicllin susceptible *Staphylococcus aureus* (MSSA), one vancomycin resistant (VR) *Enterococcus faecalis*, one vancomycin susceptible (VS) *E. faecalis*, and one VR *E. faecium*. The isolates were tested in triplicate over three different days for each reading method (i.e., VIZION and OptiRead) for a total of 468 data points for each.

The Sensititre AIM was used for plate inoculation. The mode MIC value was predetermined and the reproducibility was calculated based on MIC values falling within ±1 dilution of the mode MIC value. All MIC results were on-scale by both reading methods. Reproducibility was greater than 95% for both the VIZION and the OptiRead methods. The results were acceptable.

b. Linearity/assay reportable range:

Not Applicable

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

**Non-fastidious Gram Negative Organisms**

The CLSI recommended QC strains, *E. coli* ATCC 25922 and *P. aeruginosa* ATCC 27853 were tested a sufficient number of times (i.e., at least 20/site) at each testing site.

**Non-fastidious Gram Positive Organisms**

The CLSI recommended QC strains, *Staphylococcus aureus* ATCC 29213 and *Enterococcus faecalis* ATCC 29212 were tested a sufficient number of times (i.e., at least 20/site) at each testing site.

The results are summarized in Table 2 below. Results for all the quality control strains were within the acceptable range.

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Table 2: Quality Control (Eravacycline)

|  Organism | Conc. (μg/mL) | Reference | Sensititre  |   |
| --- | --- | --- | --- | --- |
|   |   |   |  OptiRead | VIZON  |
|  Gram Negative QC Isolates  |   |   |   |   |
|  E. coli ATCC 25922
Expected Result: 0.03 – 0.12 μg/mL | 0.008 |  |  |   |
|   |  0.015 |  |  |   |
|   |  0.03 |  |  |   |
|   |  0.06 | 72 | 58 | 56  |
|   |  0.12 | 8 | 22 | 24  |
|   |  0.25 |  |  |   |
|  |   |   |   |   |
|  P. aeruginosa
ATCC 27853
Expected Result: 2 – 16 μg/mL | 1 |  |  |   |
|   |  2 | 39 | 72 | 67  |
|   |  4 | 41 | 8 | 13  |
|   |  8 |  |  |   |
|   |  16 |  |  |   |
|   |  32 |  |  |   |
|  |   |   |   |   |
|  Gram-Positive QC Isolates  |   |   |   |   |
|  Staphylococcus aureus
ATCC 29213
Expected Result: 0.015 – 0.12 μg/mL | 0.008 |  |  |   |
|   |  0.015 |  | 1 |   |
|   |  0.03 | 21 |  | 2  |
|   |  0.06 | 56 | 62 | 45  |
|   |  0.12 | 1 | 18 | 34  |
|   |  0.25 |  |  |   |
|  |   |   |   |   |
|  Enterococcus faecalis
ATCC 29212
Expected result: 0.015 – 0.06 μg/mL | 0.008 |  |  |   |
|   |  0.015 | 9 | 4 |   |
|   |  0.03 | 66 | 51 | 30  |
|   |  0.06 | 3 | 16 | 51  |
|   |  0.12 |  |  |   |

Growth Rate: All 408 non-fastidious Gram negative and 602 non-fastidious Gram positive isolates showed sufficient growth for MIC determination.

Purity Check Plates: Purity checks were performed each day for each clinical, challenge, reproducibility, and QC strain tested.

## Inoculum Density Check:

Inoculum density of each quality control, reproducibility, clinical, and challenge isolate was determined each day of testing. The inoculum was prepared to achieve turbidity equivalent to a 0.5 McFarland standard. They were all within acceptable range.

Non-fastidious Gram Negative Organisms: A total of 333 inoculum density checks

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were performed for each test and reference plate for clinical isolates, 75 for each for test and reference plate for challenge isolates, 160 for each test and reference panel for QC isolates, and all reproducibility isolates.

Non-fastidious Gram Positive Organisms: A total of 492 inoculum density checks were performed for each test and reference plate for clinical isolates, 108 for each for test and reference plate for challenge isolates, 162 for each test and reference panel for QC isolates, and all reproducibility isolates.

The colony counts obtained for all isolates were within acceptable range.

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:

The reference plate containing the same antibiotic and dilutions used for the comparison was prepared according to the CLSI recommendation and used as the reference method. 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.

A. Non-fastidious Gram Negative Organisms:

Clinical

Clinical testing was conducted at four sites using a total of 333 isolates. Of those, 292 and 41 fresh clinical Enterobacteriaceae isolates were from List 1 (in vitro and clinical) and List 2 (in vitro), respectively. The List 1 included E. coli (104), Klebsiella pneumoniae (84), K. oxytoca (43), Enterobacter cloacae (41), and Citrobacter freundii (20). The List 2 included Klebsiella (Enterobacter) aerogenes (20) and Citrobacter koseri (21).

Challenge

An additional 75 Enterobacteriaceae challenge isolates were tested. Of these, 65 and 10 isolates were from List 1 and List 2, respectively. Testing was conducted at one

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external site.

The List 1 challenge isolates included the following species:  $E$  coli (16), Klebsiella pneumoniae (28),  $K$  oxytoca (5), Enterobacter cloacae (11), and Citrobacter freundii (5). Of the 65 List 1 challenge isolates, 43 were non-susceptible to eravacycline by the reference method.

The List 2 challenge isolates included the following species: Klebsiella (Enterobacter) aerogenes (7) and Citrobacter koseri (3). Of the 10 List 2 challenge isolates, 4 were non-susceptible to eravacycline by the reference method.

In total, 408 combined (clinical and challenge) Enterobacteriaceae isolates were evaluated. Of these, 357 and 51 isolates were from List 1 and List 2, respectively. The EA and CA were above  $90\%$  and therefore acceptable. Because of the absence of intermediate category for Eravacycline, the very major (vmj) discrepancy/errort rate was adjusted to  $0\%$ . The performance of VIZION and OptiRead of these isolates is shown in Tables 3.1 and 3.2 below.

The growth rate for each plate read in the clinical and challenge studies was  $100\%$ .

Table 3.1: Combined (Clinical and Challenge) Performance Summary of Enterobacteriaceae- Read by VIZION *

|  Eravacycline | Total | EA N | %EA Total | Tot Eval | EA Eval | %EA Eval | CA N | % CA | #NS | Errors  |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |   |   |   |   |   |   |   |   |   |  maj | vmj  |
|  Enterobacteriaceae ≤0.5 (susceptible), --, --  |   |   |   |   |   |   |   |   |   |   |   |
|  Clinical | 333 | 333 | 100 | 333 | 333 | 100 | 327 | 98.2 | 30 | 3 | 3  |
|  Challenge | 75 | 75 | 100 | 75 | 75 | 100 | 73 | 97.3 | 17 | 0 | 2  |
|  Enterobacteriaceae Total | 408 | 408 | 100 | 408 | 408 | 100 | 400 | 98.0 | 47 | 3 | 5a  |

a Of the 47 non-susceptible isolates, the MIC of the isolates that gave very major (vmj) errors (10.6% vmj rate) were within essential agreement of the reference value; therefore the adjusted vmj rate is 0%

* EA - Essential Agreement

CA - Category Agreement

NS- Not susceptible

maj - major discrepancies

vmj- very major discrepancies

Evaluable results are those that are on-scale for both the reference panel and the Sensititre panel. Essential agreement (EA) occurs when there is agreement between the MIC result of the reference method and that of Sensititre panel within plus or minus one serial two-fold dilution of the antibiotic. Category agreement occurs when the interpretation of the result of the reference method agrees exactly with the interpretation of the Sensititre panel result.

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Table 3.2: Combined (Clinical and Challenge) Performance Summary of Enterobacteriaceae- Read by OptiRead

|  Eravacycline | Total | EA N | %EA Total | Tot Eval | EA Eval | %EA Eval | CA N | % CA | #NS | Errors  |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |   |   |   |   |   |   |   |   |   |  maj | vmj  |
|  Enterobacteriaceae ≤0.5 (susceptible), --, --  |   |   |   |   |   |   |   |   |   |   |   |
|  Clinical | 333 | 333 | 100 | 333 | 333 | 100 | 322 | 96.7 | 30 | 7 | 4  |
|  Challenge | 75 | 75 | 100 | 75 | 75 | 100 | 72 | 96.0 | 17 | 1 | 2  |
|  Enterobacteriaceae Total | 408 | 408 | 100 | 408 | 408 | 100 | 394 | 96.6 | 47 | 8 | 6^{b}  |

b Of the 47 non-susceptible isolates, the MIC of the isolates that gave vmj errors (12.8% vmj rate) were within essential agreement of the reference value; therefore the adjusted vmj rate is 0%

A comparative evaluation of performance data of the VIZION and OptiRead reading methods showed no notable differences.

Of the 357 List 1 isolates tested, 43 were non-susceptible. Four and five very major (vmj) discrepancies/errors were observed with the VIZION and OptiRead, respectively. The vmj rate was 9.3% (4/43) for VIZION and 11.6% (5/43) for OptiRead. The vmj errors were from two Enterobacter cloacae, one each from Klebsiella pneumoniae and E. coli using the VIZION, and an additional vmj error from K. oxytoca using the OptiRead. All vmj errors were one doubling dilution lower but within essential agreement of the reference method (i.e., reference: 1 µg/mL, Sensititre: 0.5 µg/mL). Due to the lack of intermediate breakpoint for Enterobacteriaceae with Eravacycline, the vmj errors that were within EA of the reference can be adjusted to 0% and therefore, acceptable.

Of the 51 List 2 isolates tested, 4 were non-susceptible. One vmj error was observed with Citrobacter koseri. The vmj error rate was 25% (1/4) for both the VIZION and OptiRead reading method. The vmj rate was adjusted to 0% due to the absence of an intermediate category and the MIC value within essential agreement with the reference method.

As a result, the following limitation is included in the device labeling for Enterobacteriaceae (non-fastidious Gram negative organisms):

"There were 47 Eravacycline non-susceptible Enterobacteriaceae isolates as determined by the reference method. Although within essential agreement, five and six potential very major (vmj) discrepancies were observed with the VIZION and OptiRead, respectively, due to the lack of intermediate category. When the Sensititre MIC is at the breakpoint of 0.5 µg/mL, testing should be repeated using a reference/alternative testing method prior to reporting results for Eravacycline with Enterobacter cloacae, E. coli, K. pneumoniae, or Citrobacter koseri with VIZION and Enterobacter cloacae, E. coli, K. pneumoniae, K. oxytoca, or Citrobacter koseri with OptiRead."

## MIC Trends:

MIC trend analysis is provided in Table 3.3 below. All Enterobacteriaceae isolates have on-scale MIC values in which a determination could be made of higher or lower

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values compared to the reference method. In general, Sensititre results were one-doubling dilution lower than the reference. However, C. freundii isolates were notably one-doubling dilution higher as demonstrated in Table 3.4 below when stratified by organism. As a result, the following footnote is included in the performance section of the package insert:

"Eravacycline MIC values for Citrobacter freundii tended to be one doubling dilution higher with the VIZION and the OptiRead as compared to the reference microdilution method."

Table 3.3: MIC Trends for Performance of Enterobacteriaceae

|  Eravacycline | Total | ≥2 dil. lower | 1 dil. lower | Exact | 1 dil. higher | ≥2 dil. higher  |
| --- | --- | --- | --- | --- | --- | --- |
|  Enterobacteriaceae  |   |   |   |   |   |   |
|  VIZION | 408 | 0 | 46 | 321 | 41 | 0  |
|   |   |  11.27% |   | 78.68% | 10.05%  |   |
|   |   |  Difference: -1.23%; 95% CI (-5.51, 3.05%)  |   |   |   |   |
|  OptiRead | 408 | 0 | 60 | 298 | 50 | 0  |
|   |   |  14.71% |   | 73.04% | 12.25%  |   |
|   |   |  Difference: -2.45%; 95% CI (-7.16%, 2.26%)  |   |   |   |   |

Table 3.4: MIC Trends for Performance of C. freundii

|  Eravacycline | Total | ≥2 dil. lower | 1 dil. lower | Exact | 1 dil. higher | ≥2 dil. higher  |
| --- | --- | --- | --- | --- | --- | --- |
|  Citrobacter freundii  |   |   |   |   |   |   |
|  VIZION1 | 25 | 0 | 0 | 18 | 7 | 0  |
|   |   |  0.00% |   | 72.00% | 28.00%  |   |
|  OptiRead2 | 25 | 0 | 0 | 17 | 8 | 0  |
|   |   |  0.00% |   | 68.00% | 32.00%  |   |

1 Difference between the higher and lower dilutions for VIZION/C. freundii is 28.00%; 95% CI (8.88%, 47.58%)
2 Difference between the higher and lower dilutions for OptiRead/C. freundii is: 32.00%; 95% CI (12.09%, 51.59%)

## B. Non-Fastidious Gram Positive Organisms

### Clinical

Clinical testing was conducted at four sites using a total of 494 of fresh clinical isolates which included 199 MRSA, 201 MSSA, 60 E. faecalis, and 34 E. faecium isolates.

### Challenge

An additional 108 of non-fastidious Gram positive stock organisms were tested at one site which included 50 MRSA, 50 MSSA, 5 E. faecalis, and 3 E. faecium isolates.

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In total, 602 combined (clinical and challenge) isolates were evaluated. The performance of VIZION and the adjusted discrepancy rate of these isolates is shown in Tables 4.1 and 4.2 below, respectively.

Table 4.1: Combined (Clinical and Challenge) Performance Summary of Non-Fastidious Gram Positive- Read by VIZION

|  Eravacycline | Tot | EA N | %EA Total | Total Eval | EA Eval | %EA Eval | CA N | % CA | #NS | Errors  |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |   |   |   |   |   |   |   |   |   |  maj | vmj  |
|  Staphylococcus aureus ≤0.06 (Susceptible), --, --  |   |   |   |   |   |   |   |   |   |   |   |
|  Clinical | 400 | 397 | 99.3 | 400 | 397 | 99.3 | 365 | 91.3 | 34 | 31 | 4  |
|  Challenge | 100 | 100 | 100 | 100 | 100 | 100 | 99 | 99.0 | 3 | 1 | 0  |
|  Combined | 500 | 497 | 99.4 | 500 | 497 | 99.4 | 464 | 92.8 | 37 | 32a | 4b  |
|  E. faecalis and E. faecium ≤0.06 (Susceptible), --, --  |   |   |   |   |   |   |   |   |   |   |   |
|  E. faecalis |   |   |   |   |   |   |   |   |   |   |   |
|  Clinical | 60 | 57 | 95.0 | 60 | 57 | 95.0 | 55 | 91.7 | 1 | 5 | 0  |
|  Challenge | 5 | 5 | 100 | 5 | 5 | 100 | 5 | 100 | 1 | 0 | 0  |
|  Combined | 65 | 62 | 95.4 | 65 | 62 | 95.4 | 60 | 92.3 | 2 | 5c | 0  |
|  E. faecium |   |   |   |   |   |   |   |   |   |   |   |
|  Clinical | 34 | 34 | 100 | 34 | 34 | 100 | 32 | 94.1 | 2 | 2 | 0  |
|  Challenge | 3 | 3 | 100 | 3 | 3 | 100 | 3 | 100 | 0 | 0 | 0  |
|  Combined | 37 | 37 | 100 | 37 | 37 | 100 | 35 | 94.6 | 2 | 2d | 0  |
|  Total | 602 | 596 | 99.0 | 602 | 596 | 99.0 | 559 | 92.9 | 41 | 39e | 4f  |

a Of the 463 susceptible S. aureus isolates, the MIC of 30 of the 32 isolates that gave major (maj) errors (6.9% maj error rate) were within essential agreement of the reference value; therefore the adjusted maj rate is 0.4%
b Of the 37 non-susceptible S. aureus isolates, the MIC of the 4 isolates that gave vmj errors (10.8% vmj rate) were within essential agreement of the reference value; therefore the adjusted vmj rate is 0%
c Of the 63 susceptible E. faecalis isolates, the MIC of 3 of the 5 isolates that gave maj errors (7.9% maj error rate) were within essential agreement of the reference value; therefore the adjusted maj rate is 3.2%
d Of the 35 susceptible E. faecium isolates, the MIC of the 2 isolates that gave maj errors (5.7% maj error rate) were within essential agreement of the reference value; therefore the adjusted maj error rate is 0%
e Of the 561 susceptible non-fastidious Gram positive isolates, the MIC of 35 of the 39 isolates that gave maj errors (7.0% maj error rate) were within essential agreement of the reference value, therefore the adjusted major error rate is 0.7%
f Of the 41 non-susceptible non-fastidious Gram positive isolates, the MIC of the 4 isolates that gave vmj errors (9.8% vmj rate) were within essential agreement of the reference value, therefore the adjusted vmj rate is 0%

{13}

Table 4.2: Adjusted Discrepancies (Major and Very Major) Due to the Lack of Intermediate Category for VIZION

|  Eravacycline | Major Errors |   |   | Very Major Errors  |   |   |
| --- | --- | --- | --- | --- | --- | --- |
|   |  Susceptible # | # | Rate | Non-Susceptible # | # | Rate  |
|  S. aureus  |   |   |   |   |   |   |
|  Before Adjustment | 463 | 32 | 6.9% | 37 | 4 | 10.8%  |
|  After Adjustment |   | 2 | 0.4% |   | 0 | 0%  |
|  E. faecalis  |   |   |   |   |   |   |
|  Before Adjustment | 63 | 5 | 7.9% | 2 | 0 | 0  |
|  After Adjustment |   | 2 | 3.2% |   | NA  |   |
|  E. faecium  |   |   |   |   |   |   |
|  Before Adjustment | 35 | 2 | 5.7% | 2 | 0 | 0  |
|  After Adjustment |   | 0 | 0 |   | NA  |   |
|  Non-fastidious Gram Positive Organisms Combined  |   |   |   |   |   |   |
|  Before Adjustment | 561 | 39 | 7.0% | 41 | 4 | 9.8%  |
|  After Adjustment |   | 4 | 0.7% |   | 0 | 0  |

The performance of OptiRead and the adjusted discrepancy rate of these isolates is shown in Tables 4.3 and 4.4 below, respectively.

Table 4.3: Combined (Clinical and Challenge) Performance Summary of Non-Fastidious Gram Positive- Read by OptiRead

|  Eravacycline | Tot | EA N | %EA Total | Total Eval | EA Eval | %EA Eval | CA N | % CA | #NS | Errors  |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |   |   |   |   |   |   |   |   |   |  maj | vmj  |
|  Staphylococcus aureus ≤0.06 (Susceptible), --, --  |   |   |   |   |   |   |   |   |   |   |   |
|  Clinical | 400 | 399 | 99.8 | 400 | 399 | 99.8 | 378 | 94.5 | 34 | 17 | 5  |
|  Challenge | 100 | 99 | 99.0 | 100 | 99 | 99.0 | 95 | 95.0 | 3 | 5 | 0  |
|  Combined | 500 | 498 | 99.6 | 500 | 498 | 99.6 | 473 | 94.6 | 37 | 22g | 5h  |
|  E. faecalis and E. faecium ≤0.06 (Susceptible), --, --  |   |   |   |   |   |   |   |   |   |   |   |
|  E. faecalis |   |   |   |   |   |   |   |   |   |   |   |
|  Clinical | 60 | 58 | 96.7 | 60 | 58 | 96.7 | 59 | 98.3 | 1 | 1 | 0  |
|  Challenge | 5 | 5 | 100 | 5 | 5 | 100 | 5 | 100 | 1 | 0 | 0  |
|  Combined | 65 | 63 | 96.9 | 65 | 63 | 96.9 | 64 | 98.5 | 2 | 1 | 0  |
|  E. faecium |  |  |  |  |  |  |  |  |  |  |   |
|  Clinical | 34 | 34 | 100 | 34 | 34 | 100 | 33 | 97.1 | 2 | 1 | 0  |
|  Challenge | 3 | 3 | 100 | 3 | 3 | 100 | 3 | 100 | 0 | 0 | 0  |
|  Combined | 37 | 37 | 100 | 37 | 37 | 100 | 36 | 97.3 | 2 | 1 | 0  |
|  Total | 602 | 598 | 99.3 | 602 | 598 | 99.3 | 573 | 95.2 | 41 | 24i | 5j  |

g Of the 463 susceptible S. aureus isolates, the MIC of 21 of the 22 isolates that gave maj errors (4.8% maj error rate) were within essential agreement of the reference value; therefore the adjusted major error rate is 0.2%
h Of the 37 non-susceptible S. aureus isolates, the MIC of the 5 isolates that gave vmj errors (13.5% vmj rate) were within essential agreement of the reference value; therefore the adjusted vmj rate is 0%
i Of the 561 susceptible non-fastidious Gram positive isolates, the MIC of 22 of the 24 isolates that gave maj errors (4.3% maj error rate) were within essential agreement of the reference value, therefore the adjusted major error rate is 0.4%
j Of the 41 non-susceptible non-fastidious Gram positive isolates, the MIC of the 5 isolates that gave vmj errors (12.2% vmj rate) were within essential agreement of the reference value, therefore the adjusted vmj rate is 0%

{14}

Table 4.4: Adjusted Discrepancies (Major and Very Major) Due to the Lack of Intermediate Category for OptiRead Reading Method

|  Eravacycline | Major Errors |   |   | Very Major Errors  |   |   |
| --- | --- | --- | --- | --- | --- | --- |
|   |  Susceptible # | # | Rate | Non-Susceptible # | # | Rate  |
|  S. aureus  |   |   |   |   |   |   |
|  Before Adjustment | 463 | 22 | 4.8% | 37 | 5 | 13.5%  |
|  After Adjustment |   | 1 | 0.2% |   | 0 | 0%  |
|  Non-fastidious Gram Positive Organisms Combined  |   |   |   |   |   |   |
|  Before Adjustment | 561 | 24 | 4.3% | 41 | 5 | 12.2%  |
|  After Adjustment |   | 2 | 0.4% |   | 0 | 0  |

As shown in Tables 4.1 and 4.3 above, the EA and CA were above  $90\%$  (99.0% EA for VIZION and  $99.3\%$  EA for OptiRead), and are therefore acceptable.

The CA was  $92.9\%$  and  $95.9\%$  for VIZION and OptiRead, respectively. There were major (maj) discrepancy/errors and vmj errors with both reading methods. The major (maj) rate was  $7.0\%$  (39/561) and vmj rate was  $9.8\%$  (4/41) with the VIZION; it was  $4.3\%$  (24/561) maj rate and  $12.2\%$  (5/41) vmj rate with the OptiRead.

There were a total of 500 S. aureus isolates in the studies; maj and vmj errors were observed with both reading methods: maj rate  $6.9\%$  (32/463) and vmj rate  $10.8\%$  (4/37) with the VIZION; maj rate  $4.8\%$  (22/463) and vmj rate  $13.5\%$  (5/37) with the OptiRead.

For  $E.$  faecalis and  $E.$  faecium isolates, no vmj error was observed with both reading methods. Their maj rates are acceptable by the OptiRead but exceed the acceptance criteria at 7.9% (5/63) for  $E.$  faecalis and 5.7% (2/35) for  $E.$  faecium by VIZION.

Due to the lack of intermediate breakpoints for S. aureus, E. faecalis, and E. faecium with Eravacycline, errors (maj and vmj) that were within EA of the reference can be adjusted. As a result, the following limitation is included in the device labeling for non-fastidious gram positive organisms (S. aureus, E. faecalis, and E. faecium):

"There were 561 Eravacycline susceptible gram positive (non-fastidious) isolates as determined by the reference method. Although within essential agreement, 39 and 24 potential major (maj) discrepancies were observed with the VIZION and OptiRead, respectively, due to the lack of an intermediate category. When the Sensititre MIC is at  $0.12\mu \mathrm{g / mL}$ , the non-susceptible breakpoint, testing should be repeated using a reference/alternative testing method prior to reporting results for Eravacycline with S. aureus, E. faecalis, and E. faecium for the VIZION reading method and S. aureus with the OptiRead reading method."

"There were 41 Eravacycline non-susceptible gram positive (non-fastidious) isolates as determined by the reference method. Although within essential agreement, four and five potential very major (vmj) discrepancies were observed with the VIZION and OptiRead, respectively, due to the lack of intermediate category. When the Sensititre MIC is at the breakpoint of  $0.06\mu \mathrm{g / mL}$ , testing

{15}

should be repeated using a reference/alternative testing method prior to reporting results for Eravacycline with Staphylococcus aureus with VIZION and with OptiRead."

## MIC Trends

All non-fastidious Gram positive isolates have on-scale MIC values in which a determination could be made of higher or lower values compared to the reference method. As demonstrated in Table 5 below, there was a difference in results trending higher when compared to the reference method. It was consistently one doubling dilution higher for both VIZION and OptiRead methods. For VIZION, it was 69.60% (419/602) one-doubling dilution higher while those equal to the reference (exact) was only 27.74% (167/602). It was 58.97% one dilution higher and 37.54% exact for OptiRead.

Table 5: MIC Trends for Performance of Non-Fastidious Gram Positive (S. aureus, E. faecalis, and E. faecium)

|  Eravacycline | Total | 2 dil. lower | 1 dil. lower | Exact | 1 dil. higher | 2 dil. higher  |
| --- | --- | --- | --- | --- | --- | --- |
|  VIZION | 602 | 0 | 10 | 167 | 419 | 6  |
|   |   |  0 | 1.66% | 27.74% | 69.60% | 1.00%  |
|   |   |  1.66%^{1} |   |   | 70.60%^{1}  |   |
|  OptiRead | 602 | 0 | 17 | 226 | 355 | 4  |
|   |   |  0 | 2.82% | 37.54% | 58.97% | 0.66%  |
|   |   |  2.82%^{2} |   |   | 359 (59.63%)^{2}  |   |

1 Difference between the higher and lower dilutions for VIZION is 68.94%; 95% CI (64.93%, 72.52%)
2 Difference between the higher and lower dilutions for OptiRead is 56.81%; 95% CI (52.51%, 60.80%)

It was observed that the susceptible Gram positive isolates were clustered around the Eravacycline breakpoint. There were 147 isolates (128 S. aureus and 19 Enterococcus spp.) at the breakpoint of 0.06 µg/mL by the reference method. The maj rate was 7.0% (39/561) and 4.3% (24/561) for VIZION and OptiRead, respectively. The Sensititre trends of one dilution higher raise concerns of potential maj discrepancies for Eravacycline. As a result, the following footnotes to the performance table was included:

"Eravacycline MIC values for Staphylococcus aureus, Enterococcus faecalis, and Enterococcus faecium tended to be one doubling-dilution higher with the VIZION as compared to the reference microdilution method. When the Sensititre MIC is at the non-susceptible breakpoint of 0.12 µg/mL, testing should be repeated using a reference/alternative testing method prior to reporting results for Eravacycline with S. aureus, E. faecalis, and E. faecium."

"Eravacycline MIC values for Staphylococcus aureus, Enterococcus faecalis, and Enterococcus faecium tended to be one doubling-dilution higher with the OptiRead as compared to the reference microdilution method. When the Sensititre MIC is at the non-susceptible breakpoint of 0.12 µg/mL, testing should be repeated using a reference/alternative testing method prior to reporting results for Eravacycline with S. aureus."

{16}

Gram positive isolates were initially evaluated using a dilution range of 0.001–16 µg/mL as presented in the 510(k) submission; however, during the review, the sponsor requested that the same dilution range be considered for Gram positive as the dilution range used for Gram negative organisms (i.e., 0.008–16 µg/mL). Given that all results were on-scale for Gram positive organisms using the truncated range, the data demonstrated identical performance for all parameters compared to the original analysis using the 0.001–16 µg/mL range. Therefore, the data supports the 0.008–16 µg/mL dilution range claim for Gram positive organisms.

In addition, the following sub-section is added to the Reading Test Results section of the Instruction For Use:

“b. Difficult Microdilution Endpoints

Trailing growth may occur with some organism/antimicrobic combinations. With some combinations, the MIC values may be higher by VIZION or OptiRead when compared to the reference method. This can be observed with certain antimicrobial agents like tetracyclines (e.g., Eravacycline with Staphylococcus aureus, Enterococcus faecalis, or Enterococcus faecium).”

Resistance Markers in Challenge Isolates

Resistance markers for indicated Enterobacteriaceae were provided in the submission. They consisted mostly of βeta-lactamses including ESBL (CTX-M, TEM, SHV), carbapenemases (KPC, NDM, OXA, VIM, IMP), cAmpC, pAmpC (CMY-2, ACT/MIR), OXY, and outer membrane porin (OMPC, OMPK-36).

Gram positive and Gram negative strains expressing tetracycline-specific resistance mechanisms(s) such as efflux mediated by tet(A), tet(B), and tet(K) and ribosomal protection encoded by tet(M) and tet(Q) were not available for evaluation. As a result, the information regarding these resistance mechanisms is included in the limitation sections of the device labeling:

“Gram Negative Organisms

Resistance mechanism characterization was not available for all organisms at the time comparative testing, and therefore the performance of the Sensititre Eravacycline is unknown for Enterobacteriaceae with efflux mediated by tet(A), and tet(B).

Gram Positive Organisms

Resistance mechanism characterization was not available for all organisms at the time comparative testing, and therefore the performance of the Sensititre Eravacycline is unknown for non-fastidious gram-positive (Staphylococcus aureus, Enterococcus faecalis, and Enterococcus faecium) isolates with efflux mediated by tet(K) and ribosomal protection as encoded by tet(M).”

b. Matrix comparison:

{17}

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:

The FDA susceptibility interpretive criteria for Eravacycline are listed in Table 6.

Table 6: Interpretative Criteria for Eravacycline (μg/mL)

|   | Susceptible (S) | Intermediate (I) | Resistant (R)  |
| --- | --- | --- | --- |
|  Enterobacteriaceae* | ≤0.5 | -- | --  |
|  Staphylococcus aureus | ≤0.06 | -- | --  |
|  Enterococcus faecalis and Enterococcus faecium | ≤0.06 | -- | --  |

* Clinical efficacy was shown for Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, and Klebsiella pneumoniae.

N. Proposed Labeling:

The labeling supports the finding of substantial equivalence for this device

O. Conclusion:

The submitted information in this premarket notification is complete and supports a substantial equivalence decision.

---

**Source:** [https://fda.innolitics.com/submissions/MI/subpart-b%E2%80%94diagnostic-devices/JWY/K182797](https://fda.innolitics.com/submissions/MI/subpart-b%E2%80%94diagnostic-devices/JWY/K182797)

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