VITEK2 AST-Gram Negative Delafloxacin (<=0.06->=4 ug/mL)

K183524 · bioMerieux, Inc. · LON · Mar 12, 2019 · Microbiology

Device Facts

• Record ID: K183524
• Device Name: VITEK2 AST-Gram Negative Delafloxacin (<=0.06->=4 ug/mL)
• Applicant: bioMerieux, Inc.
• Product Code: LON · Microbiology
• Decision Date: Mar 12, 2019
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 866.1645
• Device Class: Class 2

Indications for Use

VITEK® 2 AST-Gram Negative Delafloxacin is designed for antimicrobial susceptibility testing of Gram Negative bacilli and is intended for use with the VITEK® 2 and VITEK® 2 Compact Systems as a laboratory aid in the determination of in vitro susceptibility to antimicrobial agents. The VITEK® 2 Antimicrobial Susceptibility Test (AST) is intended to be used with the VITEK® 2 Systems for the automated quantitative or qualitative susceptibility testing of isolated colonies for the most clinically significant aerobic gram-negative bacilli, Staphylococcus spp., Enterococcus spp., Streptococcus spp. and clinically significant yeast.

Device Story

VITEK 2 AST-GN Delafloxacin is an automated, miniaturized, broth-based dilution system for determining minimum inhibitory concentrations (MIC) of delafloxacin against Gram-negative bacilli. Input: standardized saline suspension of clinical isolates. Operation: system fills, seals, and incubates cards containing premeasured antimicrobial concentrations; optical scanner monitors growth via light attenuation in 64 micro-wells over time. Output: MIC values and interpretive category results (S/I/R) generated automatically. Used in clinical laboratories by technicians/microbiologists. Results assist clinicians in selecting appropriate antimicrobial therapy for patients with infections caused by susceptible organisms.

Clinical Evidence

Bench testing only. Performance evaluated using 404 clinical and 206 challenge isolates (total 609 results). Overall performance: 98.0% Essential Agreement (EA) and 95.9% Category Agreement (CA). Major error rate 0.7% (2/291 susceptible isolates); minor error rate 3.7%. Growth failure rate 0.25%. Reproducibility >99%. Trending analysis showed higher MIC values for Enterobacteriaceae compared to reference method, addressed in labeling.

Technological Characteristics

Miniaturized broth microdilution card; automated optical growth monitoring; incubation up to 18 hours. Compatible with VITEK 2 and VITEK 2 Compact platforms. Quantitative measurement of MIC. No specific materials or software algorithm class (e.g., ML) specified beyond standard automated incubation/reading.

Indications for Use

Indicated for antimicrobial susceptibility testing of isolated colonies of clinically significant aerobic gram-negative bacilli, including Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa, to determine in vitro susceptibility to Delafloxacin.

Regulatory Classification

Identification

A fully automated short-term incubation cycle antimicrobial susceptibility system is a device that incorporates concentrations of antimicrobial agents into a system for the purpose of determining in vitro susceptibility of bacterial pathogens isolated from clinical specimens. Test results obtained from short-term (less than 16 hours) incubation are used to determine the antimicrobial agent of choice to treat bacterial diseases.

Special Controls

*Classification.* Class II (special controls). The special control for this device is FDA's guidance document entitled “Class II Special Controls Guidance Document: Antimicrobial Susceptibility Test (AST) Systems; Guidance for Industry and FDA.”

Predicate Devices

• VITEK® 2 AST-GN Amikacin (K172731)

Submission Summary (Full Text)

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

A. 510(k) Number:
K183524

B. Purpose for Submission:
To obtain a substantial equivalence determination for Delafloxacin for testing of Gram-negative bacilli on the VITEK 2 and VITEK 2 Compact Antimicrobial Susceptibility Test (AST) Systems

C. Measurand:
Delafloxacin ≤ 0.06 – ≥ 4 µg/mL for Enterobacteriaceae and ≤ 0.125 – ≥ 4 µg/mL for Pseudomonas aeruginosa.

D. Type of Test:
Automated quantitative or qualitative antimicrobial susceptibility test for Delafloxacin

E. Applicant:
bioMérieux, Inc.

F. Proprietary and Established Names:
VITEK 2 AST-Gram Negative Delafloxacin (≤ 0.06 – ≥ 4 µg/mL)

G. Regulatory Information:
1. Regulation section:
21 CFR 866.1645: Fully Automated Short-Term Incubation Cycle Antimicrobial Susceptibility System

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2. Classification:
Class II

3. Product code(s):
LON – Fully automated short-term incubation cycle antimicrobial susceptibility system
LTW – Susceptibility Test Cards, Antimicrobial
LTT – Panels, Test, Susceptibility, Antimicrobial

4. Panel:
Microbiology, 83

H. Intended Use/Indications for Use:

1. Intended Use (s):
The VITEK 2 Gram-negative Susceptibility Card is intended to for use with the VITEK 2 Systems in clinical laboratories as an *in vitro* test to determine the susceptibility of clinically significant aerobic Gram-negative bacilli to antimicrobial agents when used as instructed.

2. Indications for Use:
VITEK 2 AST-Gram Negative Delafloxacin is designed for antimicrobial susceptibility testing of Gram negative bacilli and is intended for use with the VITEK 2 and VITEK 2 Compact Systems as a laboratory aid in the determination of *in vitro* susceptibility to antimicrobial agents. VITEK 2 AST-Gram Negative Delafloxacin is a quantitative test. Delafloxacin has been shown to be active against most strains of the microorganisms listed below, according to the FDA label for this antimicrobial.

Active both *in vitro* and in clinical infections
- Escherichia coli
- Enterobacter cloacae
- Klebsiella pneumoniae
- Pseudomonas aeruginosa

The VITEK 2 Gram-negative Susceptibility Card is intended to for use with the VITEK 2 Systems in clinical laboratories as an *in vitro* test to determine the susceptibility of clinically significant aerobic Gram-negative bacilli to antimicrobial agents when used as instructed.

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3. Special conditions for use statement(s):

For Prescription Use Only

4. Special instrument requirements:

VITEK 2 and VITEK 2 Compact Systems using VITEK 2 Systems 9.02 software

I. Device Description:

The VITEK 2 AST card is a miniaturized, abbreviated and automated version of the doubling dilution technique for determining the minimum inhibitory concentration (MIC). Each VITEK 2 AST card contains 64 wells. A control well(s) which contain only nutrient medium is resident on all cards. The remaining wells contain premeasured portions of antimicrobials combined with the nutrient media. The isolate to be tested is diluted to a standardized concentration with 0.45% to 0.50% saline before being used to rehydrate the antimicrobial medium within the card. The VITEK 2 System will automatically dilute the bacterial suspension to prepare an inoculum for susceptibility cards. Then the VITEK 2 will fill, seal and place the card into the incubator/reader. The VITEK 2 Compact has a manual filling, sealing, and loading operation. The VITEK 2 Systems monitor the growth of each well in the card over a defined period of time (up to 24 hours for Streptococcus species). The analysis program determines when a well demonstrates growth based on attenuation of light measured by an optical scanner. This data is used to determine the minimum inhibitory concentration or "MIC" values for the anti-microbial agent. At the completion of the incubation cycle, a report is generated that contains the MIC value along with the interpretive category result for each antimicrobial contained on the card.

VITEK 2 AST-GN Delafloxacin has the following concentrations in the card: 0.06, 0.25, 0.5, and 2 µg/mL (equivalent standard method concentration by efficacy in µg/mL). The Delafloxacin MIC result ranges for the VITEK 2 are:

- ≤ 0.06 – ≥ 4 µg/mL for Enterobacteriaceae
- ≤ 0.125 – ≥ 4 µg/mL for Pseudomonas aeruginosa

J. Substantial Equivalence Information:

1. Predicate device name(s):

VITEK 2 AST-GN Amikacin

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

K172731

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# 3. Comparison with predicate:

Table 1: Comparison with Predicate Device

| Similarities | | |
| --- | --- | --- |
| Item | Device: VITEK 2 AST-GN Delafloxacin (K183524) | Predicate Device: VITEK 2 AST-GN Amikacin (K172731) |
| Intended Use | The VITEK 2 Gram-negative Susceptibility Card is intended to for use with the VITEK 2 Systems in clinical laboratories as an in vitro test to determine the susceptibility of clinically significant aerobic Gram-negative bacilli to antimicrobial agents when used as instructed. | The VITEK 2 Antimicrobial Susceptibility Test (AST) is intended to be used with the VITEK 2 Systems for the automated quantitative or qualitative susceptibility testing of isolated colonies for the most clinically significant aerobic gram-negative bacilli, Staphylococcus spp., Enterococcus spp., Streptococcus spp. and clinically significant yeast. |
| Test Method | Automated quantitative antimicrobial susceptibility test for use with the VITEK 2 and VITEK 2 Compact Systems to determine the in vitro susceptibility of Gram negative bacilli | Same |
| Inoculum | Standardized saline suspension of test organism | Same |
| Test Card | VITEK 2 Gram Negative Susceptibility Test Card | Same |
| Instrument | VITEK 2 and VITEK 2 Compact Systems | Same |
| Analysis Algorithm | Growth pattern analysis | Same |
| Differences | | |
| Antimicrobial Agent | Delafloxacin | Amikacin |
| Antimicrobial Concentrations | 0.06, 0.25, 0.5, and 2 μg/mL | 2, 4, 16, and 48 μg/mL |
| Reporting Range | Enterobacteriaceae: ≤ 0.06 – ≥ 4 μg/mL P. aeruginosa: ≤ 0.125 - ≥ 4 μg/mL | Enterobacteriaceae and P. aeruginosa: ≤ 1 – ≥ 64 μg/mL Acinetobacter spp.: ≤ 2 – ≥ 64 μg/mL |

# K. Standard/Guidance Documents Referenced (if applicable)

FDA Class II Special Controls Guidance Document: Antimicrobial Susceptibility Test (AST) Systems; Guidance for Industry and FDA (Issued August 28, 2009)
- CLSI M07-A10, "Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard-Ninth Edition" Vol. 35 No. 2 (January 2015)

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- CLSI M100, "Performance Standards for Antimicrobial Susceptibility Testing"; Twenty-eighth Edition (January 2018)

# L. Test Principle:

The VITEK 2 and VITEK 2 Compact Systems utilize automated growth-based detection using attenuation of light measured by an optical scanner. The optics in the systems uses visible light to directly measure organism growth within each of the 64 micro-wells. Transmittance optics is based on an initial light reading of a well before significant growth has begun. Every 15 minutes throughout the incubation cycle (defined period of time based on the VITEK 2 card), light transmittance readings of each well measures organism growth by the amount of light that is prevented from passing through the well. At the completion of the incubation period, the MIC values and their associated interpretive category results for each antimicrobial on the test card are displayed in an automatically generated report.

# M. Performance Characteristics (if/when applicable):

# 1. Analytical performance:

# a. Precision/Reproducibility:

A reproducibility study for the VITEK 2 AST-GN card with Delafloxacin was conducted at three external clinical sites using a panel of ten isolates of Gram-negative bacilli consistent with the indications for use. Testing was performed on three separate days and in triplicate for a total of 270 data points. The isolates tested in the reproducibility study included five Klebsiella pneumoniae pneumoniae, two $E.$ cloacae, and three $P.$ aeruginosa isolates. Inocula were prepared using both the auto-dilution and manual dilution methods for testing in the VITEK 2 System. In addition, inocula were prepared by the manual dilution method only for use with the VITEK 2 Compact. The mode MIC value was determined and the reproducibility was calculated based on MIC values that fell within $+/-$ one doubling dilution from the mode MIC value. The majority of data points were on-scale and within $\pm$ one doubling dilution agreement as compared to the mode MIC. Two data points were off-scale when tested by the VITEK 2 and the VITEK 2 Compact. The data was analyzed taking into consideration best case and worst case scenarios as described in the Class II Special Controls Guidance Document: Antimicrobial Susceptibility Test (AST) Systems. The reproducibility performance is shown in Table 2.

Table 2: Reproducibility Performance

| | VITEK 2 | | VITEK 2 Compact |
| --- | --- | --- | --- |
| | Auto-Dilution | Manual Dilution | Manual Dilution |
| Best Case | 100% | 99.63% | 100% |
| Worst Case | 100% | 99.63% | 99.63% |

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The combined reproducibility results for all three sites were acceptable.

b. Linearity/assay reportable range:

Not applicable

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

# Quality Control (QC) Testing

The CLSI recommended QC organisms (E. coli ATCC 25922 and Pseudomonas aeruginosa ATCC 27853) were tested using both the VITEK 2 card and the reference method at each site. Both the automatic dilution and manual dilution methods were used for the VITEK 2 and the manual dilution method was used for the VITEK 2 Compact.

As shown in Table 3, both the auto-dilution and the manual dilution methods for VITEK 2 and the manual dilution for VITEK 2 Compact were within the expected range $&gt;95\%$ of the time.

Table 3: Quality Control Summary Results for VITEK 2 (Auto-Dilution and Manual Dilution Methods) and VITEK 2 Compact (Manual Dilution Method)

| Delafloxacin | | VITEK 2 | | | | VITEK 2 Compact Manual Dilution | |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | | Auto-Dilution | | Manual Dilution | | | |
| Organism | Conc. (μg/mL) | Reference | Test | Reference | Test | Reference | Test |
| E. coliATCC 25922FDA/CLSIExpected Range0.008 – 0.03μg/mL(VITEK 2:≤0.06 μg/mL) | ≤0.004 | | | | | | |
| | 0.008 | | | | | | |
| | 0.015 | 35 | | 30 | | 30 | |
| | 0.03 | 80 | | 60 | | 60 | |
| | 0.06 | | | | | | |
| | ≤0.06* | | 115 | | 90 | | 90 |
| | 0.12 | | | | | | |
| | 0.25 | | | | | | |
| | ≥0.5 | | | | | | |
| P. aeruginosaATCC 27853FDA/CLSIExpected Range0.12 - 0.5μg/mL(VITEK 2:0.12 - 0.5μg/mL) | ≤0.015 | | | | | | |
| | 0.03 | | | | | | |
| | 0.06 | | | | | | |
| | 0.12 | 10 | | 7 | | 7 | |
| | ≤0.12** | | 0 | | 0 | | 0 |
| | 0.25 | 102 | 100 | 82 | 87 | 82 | 89 |
| | 0.5 | 4 | 16 | 3 | 4 | 3 | 3 |
| | 1 | | | | | | |
| | 2 | | | | | | |
| | ≥4 | | | | 1 | | |

* The lowest dilution of the VITEK 2 Delafloxacin MIC range is $\leq 0.06\mu \mathrm{g / mL}$ for Enterobacteriaceae. Obtaining this value was considered an indicator that the quality control test results were acceptable.
**The lowest dilution of the VITEK 2 Delafloxacin MC range is $\leq 0.12\mu \mathrm{g / mL}$ for $P_{\cdot}$ aeruginosa. Obtaining this value was considered an indicator that the quality control results were acceptable.

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The CLSI Delafloxacin expected ranges for *E. coli* ATCC 25922 and *P. aeruginosa* ATCC 27853 are 0.008 – 0.03 and 0.12 – 0.5 μg/mL respectively. However, the VITEK 2 MIC reporting range is ≤0.06 – ≥4 μg/mL (MIC results: ≤0.06, 0.12, 0.25, 0.5, 1, 2, ≥4 μg/mL) for *Enterobacteriaceae* and ≤0.12 – ≥4 μg/mL (MIC results: ≤0.12, 0.25, 0.5, 1, 2, ≥4 μg/mL) for *P. aeruginosa*. The two recommended QC strains tested provided off-scale with the VITEK 2 card as the acceptable ranges are lower than the lowest concentration on the card (0.06 μg/mL for *Enterobacteriaceae* and 0.12 μg/mL for *P. aeruginosa*). The quality control test results were considered acceptable for both QC strains when the MIC value of ≤0.06 μg/mL was obtained for *E. coli* ATCC 25922 and ≤0.12 μg/mL for *P. aeruginosa* ATCC 27853. Given this, bioMérieux included the following footnote indicating that QC for delafloxacin is off-scale:

&gt; VITEK 2 AST-GN Delafloxacin does not include the full CLSI/FDA recommended dilution range for QC testing with this organism.

However, during this study, all VITEK QC results for *P. aeruginosa* ATCC 27853 were either at 0.5 or 0.25 μg/mL and none gave a value of ≤0.12μg/mL (See Table 3). In addition, bioMérieux includes the CLSI broth microdilution expected range in the labeling when the VITEK 2 system range is not aligned with that of the FDA/CLSI range. The additional information is acceptable.

## Inoculum Density Control

The DensiCHEK Plus was used to standardize the inoculum to a 0.5 McFarland standard. The instrument was standardized daily with all results recorded at each site. Calibration values were within the expected range.

## Purity Check

A purity check of all organisms was performed on the dilution tube used to prepare the VITEK 2 card inoculum. Only those cultures that were pure were evaluated in the study.

## Growth Failure Rate

There was one isolate that failed to grow in the VITEK 2 card in the clinical study. Complete test results were available for 403 isolates from a total of 404 clinical isolates. The growth failure rate was 0.25% and was acceptable.

A challenge set of 206 isolates was evaluated at one site. All 206 challenge organisms grew in the VITEK 2 GN card with Delafloxacin using both the auto-dilution and manual dilution methods for the VITEK 2 and manual inoculation for the VITEK 2 Compact System.

A total of 609 VITEK 2 AST results were available.

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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:

Testing of delafloxacin on the VITEK 2 AST-Gram Negative card was performed at three external sites and on internal site using VITEK 2 Systems (PC) version 9.02. Results obtained with the bioMérieux VITEK 2 AST-Gram Negative card with Delafloxacin were compared to results obtained with the CLSI broth microdilution reference panel. The following concentrations of Delafloxacin are contained in the VITEK 2 AST-GN test card: 0.06, 0.25, 0.5, and 2 µg/mL. However, the reporting range is ≤ 0.06 – ≥4 µg/mL for Enterobacteriaceae and ≤ 0.12 – ≥4 µg/mL for Pseudomonas aeruginosa. The reference panel contained two-fold serial dilutions with a range of ≤ 0.0039 to ≥16 µg/mL. The testing conditions for the reference method consisted of the following:

- Medium – Mueller Hinton broth with appropriate dilutions of antimicrobial solution added
- Inoculum – Direct colony suspension
- Incubation – 35°C ambient air incubator; 16-20 hours

The VITEK 2 AST cards were inoculated with test organisms using the auto-dilution method (VITEK 2 System) and using the manual dilution method (VITEK 2 System and VITEK 2 Compact). All test inocula used for the VITEK 2 AST cards and the reference method were standardized using the DensiCHEK Plus instrument.

A total of 404 clinical isolates were evaluated at three sites with VITEK 2 AST – Gram Negative cards inoculated by automatic dilution and interpreted using the VITEK 2 instrument. There was one isolate that did not grow in the studies and was excluded from the study. The no growth rate was 0.25% (1/404). Most isolates were recently isolated from clinical specimen (270 isolates, 66.8%). The remainder were stock isolates (134 isolates, 33.2%). The clinical study included several species within Enterobacteriaceae that were not indicated in the FDA drug label for delafloxacin.

A total of 206 challenge organisms (147 Enterobacteriaceae and 59 P. aeruginosa)

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were evaluated at one site. The challenge set was tested with the auto-dilution and manual dilution options of the VITEK 2 System and with the manual dilution method on the VITEK 2 Compact System. Challenge isolates included E. cloacae (18 isolates), E. coli (12 isolates), K. pneumoniae pneumoniae (14 isolates), K. pneumoniae (103 isolates), and P. aeruginosa (59 isolates).

The combined data set of clinical and challenge isolates included 609 AST results (428 Enterobacteriaceae and 181 P. aeruginosa). A total of 289 (47.4%) resistant isolates were tested among the clinical (n=130) and challenge (n=159) isolates. A sufficient number of resistant isolates from the indicated species were included.

The overall performance using the auto-dilution method of the VITEK 2 System demonstrated an EA of 98.0% and a CA of 95.9%. There were two major errors (2/291 susceptible isolates, 0.7% error rate) and 23 minor errors (23/609 total isolates, 3.7% error rate). The major error and minor error rates were acceptable. With Enterobacteriaceae isolates, performance was acceptable with an EA of 98.6% and a CA of 96.0%. With P. aeruginosa isolates, performance was acceptable with an EA of 96.7% and a CA of 95.6%. The performance based on combined clinical and challenge data was acceptable. The overall performance is shown in Table 4. In addition, there was no significant difference in performance between indicated organisms only when compared to performance of all Enterobacteriaceae isolates tested (Tables 4.1 and 4.2).

To address testing of non-indicated species the sponsor included the following statement in the Precautions section of the device labeling:

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 susceptibility information in those instances is unknown. The approved labeling for specific antimicrobial drugs provides the uses for which the antimicrobial drug is approved.

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Table 4. Performance of Clinical and Challenge Isolates, VITEK 2 Auto-Dilution Method

| Organism Type | EA Total | EA N | EA % | Eval EA Total | Eval EA N | Eval EA % | CA N | CA % | #R | Min | Maj | Vmj |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Enterobacteriaceae | | | | | | | | | | | | |
| Clinical | 281 | 275 | 97.9 | 136 | 130 | 95.6 | 267 | 95.0 | 72 | 12 | 2 | 0 |
| Challenge | 147 | 147 | 100 | 31 | 31 | 100 | 144 | 98.0 | 129 | 3 | 0 | 0 |
| Combined | 428 | 422 | 98.6 | 167 | 161 | 96.4 | 411 | 96.0 | 201 | 15 | 2 | 0 |
| P. aeruginosa | | | | | | | | | | | | |
| Clinical | 122 | 117 | 95.9 | 68 | 63 | 92.6 | 115 | 94.3 | 58 | 7 | 0 | 0 |
| Challenge | 59 | 58 | 98.3 | 30 | 29 | 96.7 | 58 | 98.3 | 30 | 1 | 0 | 0 |
| Combined | 181 | 175 | 96.7 | 98 | 92 | 93.9 | 173 | 95.6 | 88 | 8 | 0 | 0 |
| All species | | | | | | | | | | | | |
| Clinical | 403 | 392 | 97.3 | 204 | 193 | 94.6 | 382 | 94.8 | 130 | 19 | 2 | 0 |
| Challenge | 206 | 205 | 99.5 | 61 | 60 | 98.4 | 202 | 98.1 | 159 | 4 | 0 | 0 |
| Combined | 609 | 597 | 98.0 | 265 | 253 | 95.5 | 584 | 95.9 | 289 | 23 | 2 | 0 |

EA - Essential Agreement (± 1 dilution)
Min - minor discrepancies
CA - Category Agreement
Maj - major discrepancies
Eval - Evaluable isolates
Vmj - very major discrepancies
R - Resistant isolates

Essential agreement (EA) occurs when the result of the reference method and that of the VITEK card 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 VITEK card. Category agreement (CA) occurs when the interpretation of the result of the reference method agrees exactly with the interpretation provided by the VITEK card.

Table 4.1: Performance of Enterobacteriaceae Species (Indicated Species Only), Auto-dilution Method

| Delafloxacin | EA Tot | EA N | EA % | Eval EA Tot | Eval EA N | Eval EA % | CA N | CA % | #R | Min | Maj | Vmj |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Enterobacter cloacae | | | | | | | | | | | | |
| Clinical | 10 | 10 | 100 | 9 | 9 | 100 | 9 | 100 | 0 | 0 | 0 | 0 |
| Challenge | 18 | 18 | 100 | 9 | 9 | 100 | 17 | 94.4 | 13 | 1 | 0 | 0 |
| Combined | 28 | 28 | 100 | 18 | 18 | 100 | 27 | 96.4 | 13 | 1 | 0 | 0 |
| Escherichia coli | | | | | | | | | | | | |
| Clinical | 97 | 97 | 100 | 15 | 15 | 100 | 92 | 94.8 | 38 | 5 | 0 | 0 |
| Challenge | 12 | 12 | 100 | 3 | 3 | 100 | 12 | 100 | 10 | 0 | 0 | 0 |
| Combined | 109 | 109 | 100 | 18 | 18 | 100 | 104 | 95.4 | 48 | 5 | 0 | 0 |
| Klebsiella pneumoniae pneumoniae | | | | | | | | | | | | |
| Clinical | 4 | 4 | 100 | 2 | 2 | 100 | 4 | 100 | 1 | 0 | 0 | 0 |
| Challenge | 14 | 14 | 100 | 7 | 7 | 100 | 13 | 92.9 | 9 | 1 | 0 | 0 |
| Combined | 18 | 18 | 100 | 9 | 9 | 100 | 17 | 94.4 | 10 | 1 | 0 | 0 |
| Klebsiella pneumoniae | | | | | | | | | | | | |
| Clinical | 52 | 47 | 90.4 | 31 | 26 | 83.9 | 50 | 96.2 | 14 | 1 | 1 | 0 |
| Challenge | 103 | 103 | 100 | 12 | 12 | 100 | 102 | 99.0 | 97 | 1 | 0 | 0 |
| Combined | 155 | 150 | 96.8 | 43 | 38 | 88.4 | 152 | 98.1 | 111 | 2 | 1 | 0 |
| Enterobacteriaceae (all) | | | | | | | | | | | | |
| Clinical | 163 | 158 | 96.9 | 57 | 52 | 91.2 | 156 | 95.7 | 53 | 6 | 1 | 0 |
| Challenge | 147 | 147 | 100 | 31 | 31 | 100 | 144 | 98.0 | 129 | 3 | 0 | 0 |
| Combined | 310 | 305 | 98.4 | 88 | 83 | 94.3 | 300 | 96.8 | 182 | 9 | 1 | 0 |

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Table 4.2: Performance of Delafloxacin, Comparison Between Indicated Species and All Species within Enterobacteriaceae

| | EA Total | EA# | EA% | Eval EA Tot | Eval EA# | Eval EA% | CA# | CA % | #R | Min | Maj | Vmj |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Indicated Species | 310 | 305 | 98.4 | 88 | 83 | 94.3 | 300 | 96.8 | 182 | 9 | 1 | 0 |
| All Species within Enterobacteriaceae | 428 | 422 | 98.6 | 167 | 161 | 96.4 | 411 | 96.0 | 201 | 15 | 2 | 0 |

Challenge Data – Auto and Manual Dilution

The challenge data set was evaluated at one site with both the auto-dilution and manual dilution options of the VITEK 2 System and with the manual dilution method on the VITEK 2 Compact System. The performance was acceptable. Overall performance is shown in Table 5, and performances with $P$ aeruginosa and Enterobacteriaceae isolates are shown in Table 6 and Table 7, respectively.

Table 5. Performance of Challenge Isolates, VITEK 2 and VITEK 2 Compact – All Organisms

| Dilution | EA Total | EA % | EA % | Eval EA Total | Eval EA % | Eval EA % | CA % | CA % | #R | Min | Maj | Vmj |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| VITEK 2 System | | | | | | | | | | | | |
| Auto | 206 | 205 | 99.5 | 61 | 60 | 98.4 | 202 | 98.1 | 159 | 4 | 0 | 0 |
| Manual | 206 | 203 | 98.5 | 61 | 58 | 95.1 | 200 | 97.1 | 159 | 5 | 1 | 0 |
| VITEK 2 Compact | | | | | | | | | | | | |
| Manual | 206 | 206 | 100 | 61 | 61 | 100 | 202 | 98.1 | 159 | 4 | 0 | 0 |

Table 6. Performance of Challenge Isolates, VITEK 2 and VITEK 2 Compact – $P$ aeruginosa

| Dilution | EA Total | EA % | EA % | Eval EA Total | Eval EA % | Eval EA % | CA % | CA % | #R | Min | Maj | Vmj |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| VITEK 2 System | | | | | | | | | | | | |
| Auto | 59 | 58 | 98.3 | 30 | 29 | 96.7 | 58 | 98.3 | 30 | 1 | 0 | 0 |
| Manual | 59 | 57 | 96.6 | 31 | 29 | 93.5 | 57 | 96.6 | 30 | 2 | 0 | 0 |
| VITEK 2 Compact | | | | | | | | | | | | |
| Manual | 59 | 59 | 100 | 31 | 31 | 100 | 58 | 98.3 | 30 | 1 | 0 | 0 |

Table 7. Performance of Challenge Isolates, VITEK 2 and VITEK 2 Compact - Enterobacteriaceae

| Dilution | EA Total | EA % | EA % | Eval EA Total | Eval EA % | Eval EA % | CA % | CA % | #R | Min | Maj | Vmj |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| VITEK 2 System | | | | | | | | | | | | |
| Auto | 147 | 147 | 100 | 31 | 31 | 100 | 144 | 98.0 | 129 | 3 | 0 | 0 |
| Manual | 147 | 146 | 99.3 | 30 | 29 | 96.7 | 143 | 97.3 | 129 | 3 | 1 | 0 |
| VITEK 2 Compact | | | | | | | | | | | | |
| Manual | 147 | 147 | 100 | 30 | 30 | 100 | 144 | 98.0 | 129 | 3 | 0 | 0 |

MIC Trends:

An analysis of trending was conducted using the combined clinical and challenge data for each organism group. This trending calculation considers MIC values that are determined to be one or more doubling dilutions lower or higher compared to the reference method regardless of whether the device MIC values are on-scale. Results

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that are not clearly at least one dilution lower, at least one dilution higher or in exact agreement with the CLSI reference method are not considered in the trending analysis.

Trending analysis results are shown in Table 8; results were stratified by species to assess species-related trends. Species for which the difference between the percentage of isolates with higher or lower readings was $\geq 30$ with a statistically significant confidence interval were considered to show evidence of trending. Trending that provides higher or lower MIC values compared to the reference method is addressed in labeling.

There was no trending noted for $P$ aeruginosa, however, when Enterobacteriaceae species were analyzed separately and combined, trends for higher MIC values compared to the reference were observed (Table 8). The following footnote was added to the performance table in the package insert to address trending:

MIC values tended to be in exact agreement or at least one doubling dilution higher when Enterobacteriaceae isolates compared to the reference micro-dilution.

Table 8. MIC Trending Analysis of All Organisms (Clinical and Challenge)

| Organism | Total Evaluable For Trending | ≥1 Dilution Lower No. (%) | Exact No. (%) | ≥1 Dilution Higher No. (%) | Percent Difference* (95% CI) | Trending Noted |
| --- | --- | --- | --- | --- | --- | --- |
| E. cloacae | 18 | 1 (5.56) | 7 (38.9) | 10 (55.6) | 50 (20.3 to 70.4) | Yes |
| E. coli | 23 | 0 (0) | 11 (47.8) | 12 (52.2) | 47.8 (24.3 to 67.0) | Yes |
| K. pneumoniae pneumoniae | 10 | 0 (0) | 7 (70) | 3 (30) | 30.0 (3.8 to 60.3) | Yes |
| K. pneumoniae | 42 | 3 (7.1) | 19 (45.2) | 20 (47.6) | (21.9 to 55.9) | Yes |
| All Enterobacteriaceae | 93 | 4 (4.3) | 44 (47.3) | 45 (48.4) | 44.1 (32.4 to 54.4) | Yes |
| P. aeruginosa | 102 | 11 (10.8) | 64 (62.8) | 27 (26.5) | 15.7 (5.0 to 26.1) | No |

* A positive percent difference indicates a higher MIC value compared to the reference method. A negative percent difference indicates a lower MIC value compared to the reference method.

b. Matrix comparison:

Not applicable

{12}

3. Clinical studies:

Not applicable

4. Clinical cut-off:

Not applicable

5. Expected values/Reference range:

Table 6: Interpretive Criteria for Delafloxacin (FDA STIC Webpage*)

| Organism | FDA Interpretive Criteria for Delafloxacin MIC (μg/mL) | | |
| --- | --- | --- | --- |
| | S | I | R |
| Enterobacteriaceae | ≤0.25 | 0.5 | ≥1 |
| Pseudomonas aeruginosa | ≤0.5 | 1 | ≥2 |

* FDA STIC Webpage
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm410971.htm

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